Ivig modulation of chemokines for treatment of multiple sclerosis, alzheimer&#39;s disease, and parkinson&#39;s disease

ABSTRACT

The present invention provides methods for providing a prognosis of treatment of diseases associated with inflammatory disease of the brain, including MS, e.g., relapsing-remitting multiple sclerosis (RRMS), Alzheimer&#39;s disease, and Parkinson&#39;s disease using molecular markers that are shown to be overexpressed or underexpressed in patients treated with intravenous immunoglobulins (IVIG). Also provided are methods to identify compounds that are useful for the treatment or prevention of MS, e.g., relapsing-remitting multiple sclerosis (RRMS), Alzheimer&#39;s disease, and Parkinson&#39;s disease.

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application is a continuation of U.S. Ser. No. 12/189,367, filed Aug. 11, 2008, which claims priority to U.S. Ser. No. 60/955,610, filed Aug. 13, 2007, herein incorporated by reference in its entirety.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

NOT APPLICABLE

REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAM LISTING APPENDIX SUBMITTED ON A COMPACT DISK

NOT APPLICABLE

BACKGROUND OF THE INVENTION

Multiple sclerosis (MS) is the most common autoimmune inflammatory disease of the central nervous system. It is characterized by demyelinating lesions in the white matter of the central nervous system that lead to neurological deficits (Sospedra M. and Martin R., Immunology of Multiple Sclerosis. Annu Rev Immunol., 23:683-747 (2005)). The pathogenesis of the disease is associated with the infiltration of immune cells, mainly activated T cells, into the brain (Sospedra M. and Martin R., Annu Rev Immunol., 23:683-747 (2005)). This infiltration is accompanied by a disruption of the blood-brain barrier (van Horssen J. et al., J Neuropathol Exp Neurol., 66:321-8 (2007)).

Intravenous immunoglobulins (IVIG) have been shown to be effective in the treatment of a number of autoimmune diseases including MS (Sospedra M. and Martin R., Immunology of Multiple Sclerosis. Annu Rev Immunol., 23:683-747 (2005)), but the exact mechanisms of action underlying the immunomodulatory activities of IVIG have not been fully explained. There are several models that try to explain the immunomodulatory efficacy of IVIG in patients suffering from autoimmune and inflammatory diseases (Kazatchkine M. D. et al., Mult Scler, 2:24-6; 33:24-26 (2000); Trebst C. and Stangel M., Curr. Pharm. Design, 12:241-2493 (2006)). These models include Fcγ-receptor-mediated immunomodulation (SOrensen P. S., Neurol Sci, 4:227-230 (2003)), modulation of idiotype/anti-idiotype networks (Samuelsson A. et al., Science, 291:484-6 (2001)), elimination of immunostimulating microbial products (Dalakas M. C., Ann Intern Med, 126:721-30 (1997)) and neutralizing antibodies against cytokines and chemokines (Bayry J. et al., Transfus Clin Biol., 10:165-9 (2003)). IVIG's potential to modify the balance between Th1 and Th2 cell immunoreactivity and to inhibit the formation of antibody/complement complexes have also been demonstrated (Andersson U. et al., Immunol Rev, 139:21-42 (1994); Bayry J. et al., Intravenous immunoglobulin in autoimmune disorders: An insight into the immunregulatory mechanisms).

The beneficial effects of IVIG in patients with MS were shown by a number of open clinical trials (Basta M. et al., Blood, 77:376-80 (1991)) and by four randomized double-blind clinical studies (SOrensen P. S. et al., Eur J Neurol, 9:557-563 (2002); Strasser-Fuchs S. et al., Mult Scler, 2:9-13 (2000); Sorensen P. S. et al., Neurology, 50:1273-1281 (1998); Lewanska M. et al., Eur J Neurol, 9:565-572 (2002)). IVIG decreased the relapse rate in MS patients and the number of gadolinium-enhancing lesions seen on brain magnetic resonance imaging (MRI) (Dudesek A. and Zettl U. K., J Neurol, 253; V/50-V/58)). Furthermore, IVIG was shown to suppress proliferation of activated peripheral T cells (Bayry J. et al., Neurol Sci, 4:217-221 (2003); Stangel M. and Gold R., Nervenarzt, (2005)). Auto-reactive peripheral T cells can cross the blood-brain barrier and are believed to be the main effector cells responsible for brain inflammation (Sospedra M. and Martin R., Annu Rev Immunol., 23:683-747 (2005); Helling N. et al., Immunol Res., 1:27-51 (2002)). Therefore, a modulation of T cell function by IVIG could explain the beneficial therapeutic effect of IVIG seen in MS patients.

Recently, we showed that IVIG is an effective alternative treatment for patients with acute exacerbations in relapsing-remitting multiple sclerosis (RRMS) (Elovaara I. et al., Intravenous Immunoglobulin is effective and well tolerated in the treatment of MS Relapse, manuscript submitted). Because peripheral auto-reactive T cells are believed to be responsible for brain inflammation in MS, we undertook to identify genes that are differentially regulated in peripheral T cells of patients with MS in acute exacerbation that are treated with IVIG. We reasoned that differences in gene expression profiles could provide important information about the potential mechanisms of action of IVIG treatment. Furthermore, changes in gene expression profiles could provide prognostic markers to predict treatment success. Such markers could also help to identify targets for developing new therapeutic agents.

Furthermore, increasing evidence has suggested a role for brain inflammation not only in MS but also in the pathogenesis of Alzheimers' disease and Parkinsons' disease (see, e.g., Wilms et al., Curr. Pharm. Des. 13:1925 (2007)). In particular microglia, the resident innate immune cells, play a major role in inflammatory processes of the brain and are known to be associated not only with MS but also with Alzheimers' disease and in Parkinsons'disease (see, e.g, Yamamoto et al., Am. J. Pathology 166:1475 (2006); Huang et al., FASEB 19:761 (2005); Kim et al., Exp. And Mol. Med. 38:333 (2006)). Thus, the present invention provides new prognostic markers to predict treatment success associated with the administration of intravenous immunoglobulin treatment as well as new therapeutic targets that may be exploited in the treatment of MS, e.g., relapsing-remitting multiple sclerosis (RRMS), Parkinsons' disease or Alzheimers disease.'

BRIEF SUMMARY OF THE INVENTION

The present invention provides methods for providing a prognosis of treatment of multiple sclerosis, Parkinson's disease and Alzheimer's disease using molecular markers that are overexpressed or underexpressed in patients treated with intravenous immunoglobulins (IVIG). Also provided are methods to identify compounds that are useful for the treatment or prevention of multiple sclerosis. In some aspects, the subtype of multiple sclerosis is relapsing-remitting multiple sclerosis (RRMS).

Accordingly, in one embodiment the present invention provides method of providing a prognosis of multiple sclerosis, Parkinson's disease and Alzheimer's disease in a subject treated with intravenous immunoglobulin (IVIG) by contacting a biological sample from the subject treated with IVIG with a reagent that specifically binds to at least one marker selected from any of the nucleic acids and corresponding protein sequences shown in Table 3a, Table 3b, and Table 4, and then determining whether or not the marker is overexpressed or underexpressed in the sample, thus providing a prognosis for MS, Parkinson's disease and Alzheimer's disease in a subject treated with IVIG. In an aspect of this embodiment, the multiple sclerosis is of the relapsing-remitting multiple sclerosis (RRMS) subtype.

In various aspects of this embodiment, the reagent is an antibody, such as a monoclonal antibody. Alternatively, the reagent can be a nucleic acid, including an oligonucleotide or an RT PCR primer set. In other aspects, the sample is a blood sample, which can contain T cells. The sample can also be cerebrospinal fluid. In some aspects of this embodiment, one of the markers is a chemokine. Examples of chemokines include: CXCL3, CXCL5, CCL13, and XCL2.

Another embodiment of the invention provides a method of identifying a compound that prevents or treats multiple sclerosis, Parkinson's disease and Alzheimer's disease by contacting a compound with a sample comprising a cell that expresses a marker selected from any of the nucleic acid and corresponding protein sequences shown in Table 3a, Table 3b, Table 3c, Table 3d, and Table 4, and then determining the functional effect of the compound on the marker, thus identifying a compound that prevents or treats MS, Parkinson's disease and Alzheimer's disease. In an aspect of this embodiment, the multiple sclerosis is of the relapsing-remitting multiple sclerosis (RRMS) subtype.

In various aspects of this embodiment, the functional effect is an increase or decrease in expression of the marker. In other aspects, the functional effect is an increase or decrease in activity of the marker. Examples of compounds used in various aspects of this embodiment include: a small molecule, a siRNA, a ribozyme, an antibody, which can be a monoclonal antibody.

A further embodiment of the invention provides a method of treating or preventing multiple sclerosis, Parkinson's disease and Alzheimer's disease in a subject by administering to the subject an effective amount of an antibody which binds a chemokine, including CXCL5, CXCL3, and CCL13, in which the effective amount is sufficient to inactivate the chemokine or chemokine cell signaling, thus treating or preventing multiple sclerosis, Parkinson's disease and Alzheimer's disease. In an aspect of this embodiment, the multiple sclerosis is of the relapsing-remitting multiple sclerosis (RRMS) subtype.

A yet further embodiment of the invention provides a method of treating or preventing multiple sclerosis, Parkinson's disease and Alzheimer's disease in a subject by administering to the subject an effective amount of an antibody which binds a chemokine receptor, including receptors for CXCL5, CXCL3, and CCL13, in which the effective amount is sufficient to inactivate the function of the chemokine receptor, thus treating or preventing multiple sclerosis, Parkinson's disease and Alzheimer's disease. In an aspect of this embodiment, the multiple sclerosis is of the relapsing-remitting multiple sclerosis (RRMS) subtype.

Another embodiment of this invention provides a method of treating or preventing multiple sclerosis, Parkinson's disease and Alzheimer's disease in a subject by administering to the subject an effective amount of an antibody which binds to a XCL2 chemokine receptor, in which the effective amount is sufficient to activate the XCL2 chemokine receptor, thus treating or preventing multiple sclerosis, Parkinson's disease and Alzheimer's disease. In an aspect of this embodiment, the multiple sclerosis is of the relapsing-remitting multiple sclerosis (RRMS) subtype.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows development of EDSS scores in 10 RRMS patients during treatment with IVIG. Box plots containing the median, 25% and 75% percentile, minimum and maximum, demonstrate the EDSS scores of patients during remission, as well as before and after treatment with IVIG during relapse.

FIG. 2 shows that treatment with IVIG does not alter the cellular composition of cells obtained for isolation of RNA. Relative gene expression data obtained from microarray analysis are presented for CD3, CD4, CD8 and CD14. Gene expression on day 0 was set as 1 and compared with gene expression on day 6 (A) and day 26 (B). Each point represents an individual patient.

FIG. 3 shows real-time PCR demonstrating the expression of representative genes. Box plots containing the median, 25% and 75% percentile, minimum and maximum, demonstrate the relative expression of the indicated genes. Expression of genes was normalized to an endogenous control (glyceraldhyde-3-phosphate dehydrogenase). Real-time PCR experiments were done in triplets and confirmed at least two times on different days.

DETAILED DESCRIPTION OF THE INVENTION

Multiple sclerosis (MS) refers generally to an inflammatory, demyelinating disease that affects the central nervous system (CNS). During the progression of MS, the myelin surrounding the axons of neurons degenerates, resulting in subsequent axonal degeneration. The pathogenesis of MS is believed to involve an autoimmune response in which T cells attack parts of the central nervous system, triggering inflammatory responses, which results in the stimulation of other immune cells and the secretion of soluble factors such as cytokines and antibodies. The inflammatory processes triggered by T cells create leaks in the blood-brain barrier formed by endothelial cells. The leaks in the blood-brain barrier, in turn, cause a number of other damaging effects such as brain swelling, activation of macrophages, and further secretion of cytokines and other proteolytic proteins such as matrix metalloproteinases. The final outcome of these pathological processes is neuronal demyelination. See, e.g., Calabresi, P. A., American Family Physician, 70: 1935-1944 (2004), for review.

As MS progresses, gradual demyelination and transection of neuron axons in patches throughout the brain and spinal cord occur. Thus, the term multiple sclerosis refers to the multiple scars (or scleroses) found on myelin sheaths in affected individuals. This scarring causes symptoms which may vary widely depending upon the extent of scarring and which neuronal pathways are disrupted.

Among the symptoms and manifestations of MS include changes in sensation (hypoesthesia), muscle weakness, abnormal muscle spasms, difficulties in movement; difficulties with coordination and balance (ataxia); problems in speech (dysarthria) or swallowing (dysphagia), visual problems (nystagmus, optic neuritis, or diplopia), fatigue and acute or chronic pain syndromes, bladder and bowel difficulties, cognitive impairment, or emotional symptomatology (e.g., depression).

The most common initial symptoms reported are: changes in sensation in the arms, legs or face (33%), complete or partial vision loss (optic neuritis) (16%), weakness (13%), double vision (7%), unsteadiness when walking (5%), and balance problems (3%). See Navarro et al., Rev Neurol 41: 601-3 (2005); Jongen P., J Neurol Sci 245: 59-62 (2006). In some individuals, the initial MS attack is preceded by infection, trauma, or strenuous physical effort.

A number of diagnostic tests are currently in use for the diagnosis of MS. These include the clinical presentation of two separate episodes of neurologic symptoms characteristic of MS, along with the finding of consistent abnormalities on physical examination. Alternatively, magnetic resonance imaging (MRI) of the brain and spine is often used to evaluate individuals with suspected MS. MRI reveals areas of demyelination as bright lesions on T2-weighted images or FLAIR (fluid attenuated inversion recovery) sequences. Gadolinium contrast can be used to demonstrate active plaques on T1-weighted images.

The testing of cerebrospinal fluid (CSF) can provide evidence of chronic inflammation of the central nervous system, a characteristic of MS. In such a test, the CSF is tested for oligoclonal bands, which are immunoglobulins found in 85% to 95% of people with definite MS. When combined with MRI and clinical data, the presence of oligoclonal bands can help make a definite diagnosis of MS.

Because the brains MS-affected individuals often respond less actively to stimulation of the optic nerve and sensory nerves, the measurement of such brain responses can also be used as a diagnostic tool. These brain responses can be examined using visual evoked potentials (VEPs) and somatosensory evoked potentials (SEPs). Decreased activity on either test can reveal demyelination which may be otherwise asymptomatic. Along with other data, these exams can help uncover the widespread nerve involvement required for a definite diagnosis of MS.

Several subtypes, or patterns of progression, of MS have been described. In 1996, the United States National Multiple Sclerosis Society standardized the following four subtype definitions, as described below.

Relapsing-remitting MS (RRMS) refers to a subtype characterized by unpredictable attacks (relapses) followed by periods of months to years of relative quiet (remission) with no new signs of disease activity. Deficits suffered during the attacks may either resolve or may be permanent. Relapsing-remitting describes the initial course of 85% to 90% of individuals with MS.

Secondary progressive describes around 80% of those with initial relapsing-remitting MS, who then begin to have neurologic decline between their acute attacks without any definite periods of remission. This decline may include new neurologic symptoms, worsening cognitive function, or other deficits. Secondary progressive is the most common type of MS and causes the greatest amount of disability.

Primary progressive describes the approximately 10% of individuals who never have remission after their initial MS symptoms. Decline occurs continuously without clear attacks. The primary progressive subtype tends to affect people who are older at disease onset.

Progressive relapsing describes those individuals who, from the onset of their MS, have a steady neurologic decline but also suffer superimposed attacks; and is the least common of all subtypes.

While there is currently no definitive cure for MS, a number of therapies have been developed that are directed toward returning function after an attack, preventing new attacks, or preventing disability. Thus, different therapies are used for patients experiencing acute attacks; those who have the relapsing-remitting subtype; those who have the progressive subtypes; those without a diagnosis of MS who have a demyelinating event; and for managing the various consequences of MS attacks.

The phamacological agents currently in use for MS include interferons, which have been approved for use in relapsing forms of secondary progressive MS; glatiramer acetate, a synthetic medication made of four amino acids that are found in myelin, which stimulates T cells to secrete anti-inflammatory agents that reduce inflammation at lesion sites; mitoxantrone, an agent used to treat progressive, progressive-relapsing, and worsening relapsing-remitting MS; and Natalizumab, a monoclonal antibody that recognizes α4-integrin.

High doses of intravenous corticosteroids, such as methylprednisolone, are frequently administered in the treatment of RRMS and have been shown to be effective at shortening the length of relapsing-remitting symptomatic attacks. As described in greater detail herein, intravenous IgG immunoglobulins have also been used to treat MS.

Similarly to MS, other disease states are associated with brain inflammation, such as Parkinson's disease and Alzheimer's disease, as described above. For example, chemokine CCL13, described herein, activates the chemokine receptor CCR2, which is expressed in microglia and astrocytes. Both of these cell types are associated with Parkinson's disease and Alzheimer's disease. This and other markers described herein are therefore useful for drug assays, diagnostic and prognostic assays, and for therapeutic siRNA and antibody treatment for Alzheimer's disease and Parkinson's disease.

Intravenous immunoglobulins (IVIG) have been successfully used to treat a number of autoimmune diseases of the central nervous system, including multiple sclerosis (MS). However, the underlying mechanisms of action of IVIG have not been fully explained. Accordingly, we have undertaken the identification of gene expression profiles that are associated with the immunomodulatory activity of IVIG in patients with acute exacerbations in relapsing-remitting MS (RRMS). As described below, HU-133 microarrays from Affymetrix were used to study gene expression profiles of peripheral T cells in 10 RRMS patients before and after treatment with IVIG. Patients treated with intravenous methylprednisolone were included as controls. The differential expression of representative genes was confirmed by real-time polymerase chain reaction. All patients were analyzed neurologically and by brain and spinal cord magnetic resonance imaging before and after IVIG therapy.

As shown below in the Examples, 360 genes that were differentially expressed during IVIG treatment were identified. Some encode chemokines such as CXCL3 and CXCL5 that are known to bind to CXCR2, a receptor essential for the regulation of oligodendrocyte migration in the brain. Others encode proteins that are involved in signal transduction, proliferation or apoptosis.

The studies disclosed herein indicate that among the differentially expressed genes the regulation of chemokine expression in peripheral T cells is an important new mechanism of action of IVIG in patients with acute exacerbations in MS. Thus, the genes disclosed herein may serve as diagnostic markers for predicting treatment success in IVIG therapy and provide new molecular targets for drug development.

DEFINITIONS

The term “intravenous IgG” or “IVIG” treatment refers generally to a composition of IgG immunoglobulins administered intravenously to treat a number of conditions such as immune deficiencies, inflammatory diseases, and autoimmune diseases. The IgG immunoglobulins are typically pooled and prepared from serum. Whole antibodies or fragments can be used.

The term “chemokine” refers generally to a family of small cytokines which are secreted by various cells that promote chemotaxis in responsive cells. Chemokines have also gone by the nomenclature of SIS family of cytokines, SIG family of cytokines, SCY family of cytokines, Platelet factor-4 superfamily or intercrines. Cells that are attracted by chemokines follow a signal of increasing chemokine concentration towards the source of the chemokine.

Some members of the chemokine family control cells of the immune system during the process of immune surveillance, such as by directing lymphocytes to the lymph nodes to allow lymphocyte surveillance invasion of pathogens through interaction with antigen-presenting cells residing in these tissues. Such chemokines are known as homeostatic chemokines and are produced and secreted without any need to stimulate their source cell(s). Some chemokines have roles in development by, e.g., promoting angiogenesis or guiding cells to tissues that provide specific signals critical for cellular maturation. Other chemokines are inflammatory and are released from a wide variety of cells in response to bacterial infection, viruses and agents that cause physical damage. The release of inflammatory chemokines is often stimulated by pro-inflammatory cytokines such as interleukin 1. Inflammatory chemokines function mainly as chemoattractants for leukocytes, recruiting monocytes, neutrophils and other effector cells from the blood to sites of infection or tissue damage. Certain inflammatory chemokines activate cells to initiate an immune response or promote wound healing. They are released by many different cell types and serve to guide cells of both innate immune system and adaptive immune system.

Structurally, chemokines are small proteins, with molecular masses of between 8 and 10 kDa. Chemokines also possess conserved amino acids that are important for creating their 3-dimensional or tertiary structure, such as (in most cases) four cysteines that interact with each other in pairs to create a greek key shape that is a characteristic of this class of proteins; intramolecular disulphide bonds typically join the first to third, and the second to fourth cysteine residues, numbered as they appear in the protein sequence of the chemokine.

Members of the chemokine family are categorized into four groups depending on the spacing of their first two cysteine residues. The CC chemokines (or β-chemokines) have two adjacent cysteines near their amino terminus. There have been at least 27 distinct members of this subgroup reported for mammals, called CC chemokine ligands (CCL)-1 to -28. The first two cysteine residues in CXC chemokines (or α-chemokines) are separated by one amino acid, represented by “X”. There have been 17 different CXC chemokines described in mammals, that are subdivided into two categories, those with a specific amino acid sequence (or motif) of Glutamic acid-Leucine-Arginine (ELR) immediately before the first cysteine of the CXC motif (ELR-positive), and those without an ELR motif (ELR-negative). The third group of chemokines is known as the C chemokines (or γ chemokines), and is unlike all other chemokines in that it has only two cysteines; one N-terminal cysteine and one cysteine downstream. A fourth group has three amino acids between the two cysteines and is termed CX₃C chemokine (or δ-chemokines).

Chemokine receptors are G protein-coupled receptors containing 7 transmembrane domains that are found on the surface of leukocytes. Approximately 19 different chemokine receptors have been characterized to date, which are divided into four families depending on the type of chemokine they bind; CXCR that bind CXC chemokines, CCR that bind CC chemokines, CX3CR1 that binds the sole CX3C chemokine (CX3CL1), and XCR1 that binds the two XC chemokines (XCL1 and XCL2).

“Chemokine cell signaling” refers generally to the ability of chemokine receptors to associate with G-proteins to transmit cell signals following ligand binding. Activation of G proteins, by chemokine receptors, causes the subsequent activation of phospholipase C (PLC). PLC cleaves a phosphatidylinositol (4,5)-bisphosphate (PIP2) into two second messenger molecules, inositol triphosphate (IP3) and diacylglycerol (DAG) that trigger intracellular signaling events; DAG activates another enzyme called protein kinase C (PKC), and IP3 triggers the release of calcium from intracellular stores. These events promote signaling cascades such as the MAP kinase pathway that generate responses including chemotaxis, degranulation, release of superoxide anions and changes in the avidity of cell adhesion molecules such as integrins within the cell harboring the chemokine receptor.

The term “marker” or “biomarker” refers to a molecule (typically protein, nucleic acid, carbohydrate, or lipid) that is expressed in a cell, expressed on the surface of a cell or secreted by a cell and which is useful for providing a prognosis of relapsing-remitting multiple sclerosis (RRMS) in a subject treated with IVIG. Some of the biomarkers disclosed herein are molecules that are overexpressed in individuals with relapsing-remitting multiple sclerosis (RRMS) treated with IVIG, in comparison to individuals not treated IVIG or in RRMS patients prior to treatment with IVIG, for instance, 1-fold overexpression, 2-fold overexpression, 3-fold overexpression, or more. Alternatively, other biomarkers are molecules that are underexpressed in individuals with relapsing-remitting multiple sclerosis (RRMS) treated with IVIG, in comparison to individuals not treated IVIG or in RRMS patients prior to treatment with IVIG, for instance, 1-fold underexpression, 2-fold underexpression, 3-fold underexpression, or more. Further, a marker can be a molecule that is inappropriately synthesized in individuals with relapsing-remitting multiple sclerosis (RRMS) treated with IVIG, in comparison to individuals not treated IVIG or in RRMS patients prior to treatment with IVIG, for instance, a molecule that contains deletions, additions or mutations in comparison to the molecule expressed on a normal cell.

It will be understood by the skilled artisan that markers may be used singly or in combination with other markers for any of the uses, e.g., prognosis of IVIG treatment of relapsing-remitting multiple sclerosis (RRMS), disclosed herein.

“Biological sample” includes biological fluid samples, such as blood and cerebrospinal fluid, sections of tissues such as biopsy and autopsy samples, and frozen sections taken for histologic purposes. Such samples include blood and blood fractions or products (e.g., serum, plasma, platelets, red blood cells, and the like), cerebrospinal fluid, sputum, cervicovaginal fluid, lymph and tongue tissue, cultured cells, e.g., primary cultures, explants, and transformed cells, stool, urine, etc. A biological sample is typically obtained from a eukaryotic organism, most preferably a mammal such as a primate e.g., chimpanzee or human; cow; dog; cat; a rodent, e.g., guinea pig, rat, Mouse; rabbit; or a bird; reptile; or fish.

The terms “overexpress,” “overexpression” or “overexpressed” or “upregulated” interchangeably refer to a protein or nucleic acid (RNA) that is transcribed or translated at a detectably greater level, usually in an IVIG-treated relapsing-remitting multiple sclerosis (RRMS) patient, in comparison to a patient not undergoing IVIG treatment. The term includes overexpression due to transcription, post transcriptional processing, translation, post-translational processing, cellular localization (e.g., organelle, cytoplasm, nucleus, cell surface), and RNA and protein stability, as compared to a control. Overexpression can be detected using conventional techniques for detecting mRNA (i.e., RT-PCR, PCR, hybridization) or proteins (i.e., ELISA, immunohistochemical techniques). Overexpression can be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more in comparison to a normal cell. In certain instances, overexpression is 1-fold, 2-fold, 3-fold, 4-fold or more higher levels of transcription or translation in comparison to a control.

The terms “underexpress,” “underexpression” or “underexpressed” or “downregulated” interchangeably refer to a protein or nucleic acid that is transcribed or translated at a detectably lower level, usually in an IVIG-treated relapsing-remitting multiple sclerosis (RRMS) patient, in comparison to a patient not undergoing IVIG treatment. The term includes underexpression due to transcription, post transcriptional processing, translation, post-translational processing, cellular localization (e.g., organelle, cytoplasm, nucleus, cell surface), and RNA and protein stability, as compared to a control. Underexpression can be detected using conventional techniques for detecting mRNA (i.e., RT-PCR, PCR, hybridization) or proteins (i.e., ELISA, immunohistochemical techniques). Underexpression can be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or less in comparison to a control. In certain instances, underexpression is 1-fold, 2-fold, 3-fold, 4-fold or more lower levels of transcription or translation in comparison to a control.

The term “differentially expressed” or “differentially regulated” refers generally to a protein or nucleic acid that is overexpressed (upregulated) or underexpressed (downregulated) in one sample compared to at least one other sample, generally in an IVIG-treated relapsing-remitting multiple sclerosis (RRMS) patient, in comparison to a patient not undergoing IVIG treatment, in the context of the present invention.

“Therapeutic treatment” refers to drug therapy, hormonal therapy, immunotherapy, and biologic (targeted) therapy.

By “therapeutically effective amount or dose” or “sufficient amount or dose” herein is meant a dose that produces effects for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

The terms “identical” or percent “identity,” in the context of two or more nucleic acids or polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identity over a specified region, when compared and aligned for maximum correspondence over a comparison window or designated region) as measured using a BLAST or BLAST 2.0 sequence comparison algorithms with default parameters described below, or by manual alignment and visual inspection (see, e.g., NCBI web site http://www.ncbi.nlm.nih.gov/BLAST/ or the like). Such sequences are then said to be “substantially identical.” This definition also refers to, or may be applied to, the compliment of a test sequence. The definition also includes sequences that have deletions and/or additions, as well as those that have substitutions. As described below, the preferred algorithms can account for gaps and the like. Preferably, identity exists over a region that is at least about 25 amino acids or nucleotides in length, or more preferably over a region that is 50-100 amino acids or nucleotides in length.

For sequence comparison, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. Preferably, default program parameters can be used, or alternative parameters can be designated. The sequence comparison algorithm then calculates the percent sequence identities for the test sequences relative to the reference sequence, based on the program parameters.

A “comparison window,” as used herein, includes reference to a segment of any one of the number of contiguous positions selected from the group consisting of from 20 to 600, usually about 50 to about 200, more usually about 100 to about 150 in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned. Methods of alignment of sequences for comparison are well-known in the art. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith & Waterman, Adv. Appl. Math. 2:482 (1981), by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443 (1970), by the search for similarity method of Pearson & Lipman, Proc. Nat'l. Acad. Sci. USA 85:2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by manual alignment and visual inspection (see, e.g., Current Protocols in Molecular Biology (Ausubel et al., eds. 1987-2005, Wiley Interscience)).

A preferred example of algorithm that is suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al., Nuc. Acids Res. 25:3389-3402 (1977) and Altschul et al., J. Mol. Biol. 215:403-410 (1990), respectively. BLAST and BLAST 2.0 are used, with the parameters described herein, to determine percent sequence identity for the nucleic acids and proteins of the invention. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov/). This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive-valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul et al., supra). These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. The word hits are extended in both directions along each sequence for as far as the cumulative alignment score can be increased. Cumulative scores are calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always >0) and N (penalty score for mismatching residues; always <0). For amino acid sequences, a scoring matrix is used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a wordlength (W) of 11, an expectation (E) of 10, M=5, N=−4 and a comparison of both strands. For amino acid sequences, the BLASTP program uses as defaults a wordlength of 3, and expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff & Henikoff, Proc. Natl. Acad. Sci. USA 89:10915 (1989)) alignments (B) of 50, expectation (E) of 10, M=5, N=−4, and a comparison of both strands.

“Nucleic acid” refers to deoxyribonucleotides or ribonucleotides and polymers thereof in either single- or double-stranded form, and complements thereof. The term encompasses nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non-naturally occurring, which have similar binding properties as the reference nucleic acid, and which are metabolized in a manner similar to the reference nucleotides. Examples of such analogs include, without limitation, phosphorothioates, phosphoramidates, methyl phosphonates, chiral-methyl phosphonates, 2-O-methyl ribonucleotides, peptide-nucleic acids (PNAs).

“RNAi molecule” or an “siRNA” refers to a nucleic acid that forms a double stranded RNA, which double stranded RNA has the ability to reduce or inhibit expression of a gene or target gene when the siRNA expressed in the same cell as the gene or target gene. “siRNA” thus refers to the double stranded RNA formed by the complementary strands. The complementary portions of the siRNA that hybridize to form the double stranded molecule typically have substantial or complete identity. In one embodiment, an siRNA refers to a nucleic acid that has substantial or complete identity to a target gene and forms a double stranded siRNA. The sequence of the siRNA can correspond to the full length target gene, or a subsequence thereof. Typically, the siRNA is at least about 15-50 nucleotides in length (e.g., each complementary sequence of the double stranded siRNA is 15-50 nucleotides in length, and the double stranded siRNA is about 15-50 base pairs in length, preferable about preferably about 20-30 base nucleotides, preferably about 20-25 nucleotides in length, e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length.

An “antisense” polynucleotide is a polynucleotide that is substantially complementary to a target polynucleotide and has the ability to specifically hybridize to the target polynucleotide.

Ribozymes are enzymatic RNA molecules capable of catalyzing specific cleavage of RNA. The composition of ribozyme molecules preferably includes one or more sequences complementary to a target mRNA, and the well known catalytic sequence responsible for mRNA cleavage or a functionally equivalent sequence (see, e.g., U.S. Pat. No. 5,093,246, which is incorporated herein by reference in its entirety). Ribozyme molecules designed to catalytically cleave target mRNA transcripts can also be used to prevent translation of subject target mRNAs.

Unless otherwise indicated, a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions) and complementary sequences, as well as the sequence explicitly indicated. Specifically, degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and/or deoxyinosine residues (Batzer et al., Nucleic Acid Res. 19:5081 (1991); Ohtsuka et al., J. Biol. Chem. 260:2605-2608 (1985); Rossolini et al., Mol. Cell. Probes 8:91-98 (1994)). The term nucleic acid is used interchangeably with gene, cDNA, mRNA, oligonucleotide, and polynucleotide.

A particular nucleic acid sequence also implicitly encompasses “splice variants” and nucleic acid sequences encoding truncated forms of a protein. Similarly, a particular protein encoded by a nucleic acid implicitly encompasses any protein encoded by a splice variant or truncated form of that nucleic acid. “Splice variants,” as the name suggests, are products of alternative splicing of a gene. After transcription, an initial nucleic acid transcript may be spliced such that different (alternate) nucleic acid splice products encode different polypeptides. Mechanisms for the production of splice variants vary, but include alternate splicing of exons. Alternate polypeptides derived from the same nucleic acid by read-through transcription are also encompassed by this definition. Any products of a splicing reaction, including recombinant forms of the splice products, are included in this definition. Nucleic acids can be truncated at the 5′ end or at the 3′ end. Polypeptides can be truncated at the N-terminal end or the C-terminal end. Truncated versions of nucleic acid or polypeptide sequences can be naturally occurring or recombinantly created.

The terms “polypeptide,” “peptide” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymer.

The term “amino acid” refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an α carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid.

Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.

“Conservatively modified variants” applies to both amino acid and nucleic acid sequences. With respect to particular nucleic acid sequences, conservatively modified variants refers to those nucleic acids which encode identical or essentially identical amino acid sequences, or where the nucleic acid does not encode an amino acid sequence, to essentially identical sequences. Because of the degeneracy of the genetic code, a large number of functionally identical nucleic acids encode any given protein. For instance, the codons GCA, GCC, GCG and GCU all encode the amino acid alanine. Thus, at every position where an alanine is specified by a codon, the codon can be altered to any of the corresponding codons described without altering the encoded polypeptide. Such nucleic acid variations are “silent variations,” which are one species of conservatively modified variations. Every nucleic acid sequence herein which encodes a polypeptide also describes every possible silent variation of the nucleic acid. One of skill will recognize that each codon in a nucleic acid (except AUG, which is ordinarily the only codon for methionine, and TGG, which is ordinarily the only codon for tryptophan) can be modified to yield a functionally identical molecule. Accordingly, each silent variation of a nucleic acid which encodes a polypeptide is implicit in each described sequence with respect to the expression product, but not with respect to actual probe sequences.

As to amino acid sequences, one of skill will recognize that individual substitutions, deletions or additions to a nucleic acid, peptide, polypeptide, or protein sequence which alters, adds or deletes a single amino acid or a small percentage of amino acids in the encoded sequence is a “conservatively modified variant” where the alteration results in the substitution of an amino acid with a chemically similar amino acid. Conservative substitution tables providing functionally similar amino acids are well known in the art. Such conservatively modified variants are in addition to and do not exclude polymorphic variants, interspecies homologs, and alleles of the invention.

The following eight groups each contain amino acids that are conservative substitutions for one another: 1) Alanine (A), Glycine (G); 2) Aspartic acid (D), Glutamic acid (E); 3) Asparagine (N), Glutamine (Q); 4) Arginine (R), Lysine (K); 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V); 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W); 7) Serine (S), Threonine (T); and 8) Cysteine (C), Methionine (M). See, e.g., Creighton, Proteins (1984).

A “label” or a “detectable moiety” is a composition detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, or other physical means. For example, useful labels include ³²P, fluorescent dyes, electron-dense reagents, enzymes (e.g., as commonly used in an ELISA), biotin, digoxigenin, or haptens and proteins which can be made detectable, e.g., by incorporating a radiolabel into the peptide or used to detect antibodies specifically reactive with the peptide.

The term “recombinant” when used with reference, e.g., to a cell, or nucleic acid, protein, or vector, indicates that the cell, nucleic acid, protein or vector, has been modified by the introduction of a heterologous nucleic acid or protein or the alteration of a native nucleic acid or protein, or that the cell is derived from a cell so modified. Thus, for example, recombinant cells express genes that are not found within the native (non-recombinant) form of the cell or express native genes that are otherwise abnormally expressed, under expressed or not expressed at all.

The phrase “stringent hybridization conditions” refers to conditions under which a probe will hybridize to its target subsequence, typically in a complex mixture of nucleic acids, but to no other sequences. Stringent conditions are sequence-dependent and will be different in different circumstances. Longer sequences hybridize specifically at higher temperatures. An extensive guide to the hybridization of nucleic acids is found in Tijssen, Techniques in Biochemistry and Molecular Biology—Hybridization with Nucleic Probes, “Overview of principles of hybridization and the strategy of nucleic acid assays” (1993). Generally, stringent conditions are selected to be about 5-10° C. lower than the thermal melting point (T_(m)) for the specific sequence at a defined ionic strength pH. The T_(m) is the temperature (under defined ionic strength, pH, and nucleic concentration) at which 50% of the probes complementary to the target hybridize to the target sequence at equilibrium (as the target sequences are present in excess, at T_(m), 50% of the probes are occupied at equilibrium). Stringent conditions may also be achieved with the addition of destabilizing agents such as formamide. For selective or specific hybridization, a positive signal is at least two times background, preferably 10 times background hybridization. Exemplary stringent hybridization conditions can be as following: 50% formamide, 5×SSC, and 1% SDS, incubating at 42° C., or, 5×SSC, 1% SDS, incubating at 65° C., with wash in 0.2×SSC, and 0.1% SDS at 65° C.

Nucleic acids that do not hybridize to each other under stringent conditions are still substantially identical if the polypeptides which they encode are substantially identical. This occurs, for example, when a copy of a nucleic acid is created using the maximum codon degeneracy permitted by the genetic code. In such cases, the nucleic acids typically hybridize under moderately stringent hybridization conditions. Exemplary “moderately stringent hybridization conditions” include a hybridization in a buffer of 40% formamide, 1 M NaCl, 1% SDS at 37° C., and a wash in 1×SSC at 45° C. A positive hybridization is at least twice background. Those of ordinary skill will readily recognize that alternative hybridization and wash conditions can be utilized to provide conditions of similar stringency. Additional guidelines for determining hybridization parameters are provided in numerous reference, e.g., and Current Protocols in Molecular Biology, ed. Ausubel, et al., supra.

For PCR, a temperature of about 36° C. is typical for low stringency amplification, although annealing temperatures may vary between about 32° C. and 48° C. depending on primer length. For high stringency PCR amplification, a temperature of about 62° C. is typical, although high stringency annealing temperatures can range from about 50° C. to about 65° C., depending on the primer length and specificity. Typical cycle conditions for both high and low stringency amplifications include a denaturation phase of 90° C.-95° C. for 30 sec-2 min., an annealing phase lasting 30 sec.-2 min., and an extension phase of about 72° C. for 1-2 min. Protocols and guidelines for low and high stringency amplification reactions are provided, e.g., in Innis et al. (1990) PCR Protocols, A Guide to Methods and Applications, Academic Press, Inc. N.Y.).

“Antibody” refers to a polypeptide comprising a framework region from an immunoglobulin gene or fragments thereof that specifically binds and recognizes an antigen. The recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon, and mu constant region genes, as well as the myriad immunoglobulin variable region genes. Light chains are classified as either kappa or lambda. Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively. Typically, the antigen-binding region of an antibody will be most critical in specificity and affinity of binding. Antibodies can be polyclonal or monoclonal, derived from serum, a hybridoma or recombinantly cloned, and can also be chimeric, primatized, or humanized.

An exemplary immunoglobulin (antibody) structural unit comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one “light” (about 25 kDa) and one “heavy” chain (about 50-70 kDa). The N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The terms variable light chain (V_(L)) and variable heavy chain (V_(H)) refer to these light and heavy chains respectively.

Antibodies exist, e.g., as intact immunoglobulins or as a number of well-characterized fragments produced by digestion with various peptidases. Thus, for example, pepsin digests an antibody below the disulfide linkages in the hinge region to produce F(ab)′₂, a dimer of Fab which itself is a light chain joined to V_(H)-C_(H)1 by a disulfide bond. The F(ab)′₂ may be reduced under mild conditions to break the disulfide linkage in the hinge region, thereby converting the F(ab)′₂ dimer into an Fab′ monomer. The Fab′ monomer is essentially Fab with part of the hinge region (see Fundamental Immunology (Paul ed., 3d ed. 1993). While various antibody fragments are defined in terms of the digestion of an intact antibody, one of skill will appreciate that such fragments may be synthesized de novo either chemically or by using recombinant DNA methodology. Thus, the term antibody, as used herein, also includes antibody fragments either produced by the modification of whole antibodies, or those synthesized de novo using recombinant DNA methodologies (e.g., single chain Fv) or those identified using phage display libraries (see, e.g., McCafferty et al., Nature 348:552-554 (1990)).

An antibody immunologically reactive with a particular biomarker protein of the present invention can be generated by recombinant methods such as selection of libraries of recombinant antibodies in phage or similar vectors, see, e.g., Huse et al., Science, 246:1275-1281 (1989); Ward et al., Nature, 341:544-546 (1989); and Vaughan et al., Nature Biotech., 14:309-314 (1996), or by immunizing an animal with the antigen or with DNA encoding the antigen.

Methods of preparing polyclonal antibodies are known to the skilled artisan (e.g., Harlow & Lane, 1988, Antibodies: A Laboratory Manual. (Cold Spring Harbor Press)). Polyclonal antibodies can be raised in a mammal, e.g., by one or more injections of an immunizing agent and, if desired, an adjuvant. Typically, the immunizing agent and/or adjuvant will be injected in the mammal by multiple subcutaneous or intraperitoneal injections. The immunizing agent may include a protein encoded by a nucleic acid of the figures or fragment thereof or a fusion protein thereof. It may be useful to conjugate the immunizing agent to a protein known to be immunogenic in the mammal being immunized. Examples of such immunogenic proteins include but are not limited to keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, and soybean trypsin inhibitor. Examples of adjuvants which may be employed include Freund's complete adjuvant and MPL-TDM adjuvant (monophosphoryl Lipid A, synthetic trehalose dicorynomycolate). The immunization protocol may be selected by one skilled in the art without undue experimentation.

The antibodies can, alternatively, be monoclonal antibodies. Monoclonal antibodies may be prepared using hybridoma methods, such as those described by Kohler & Milstein, Nature, 256:495 (1975). In a hybridoma method, a mouse, hamster, or other appropriate host animal, is typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent. Alternatively, the lymphocytes may be immunized in vitro. Generally, either peripheral blood lymphocytes (“PBLs”) are used if cells of human origin are desired, or spleen cells or lymph node cells are used if nonhuman mammalian sources are desired. The lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell (Goding, Monoclonal Antibodies: Principles and Practice, pp. 59-103 (1986)). Immortalized cell lines are usually transformed mammalian cells, particularly myeloma cells of rodent, bovine and human origin. Usually, rat or mouse myeloma cell lines are employed. The hybridoma cells may be cultured in a suitable culture medium that preferably contains one or more substances that inhibit the growth or survival of the unfused, immortalized cells. For example, if the parental cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine (“HAT medium”), which substances prevent the growth of HGPRT-deficient cells.

Human antibodies can be produced using various techniques known in the art, including phage display libraries (Hoogenboom & Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991)). The techniques of Cole et al. and Boerner et al. are also available for the preparation of human monoclonal antibodies (Cole et al., Monoclonal Antibodies and Cancer Therapy, p. 77 (1985) and Boerner et al., J. Immunol., 147(1):86-95 (1991)). Similarly, human antibodies can be made by introducing of human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire. This approach is described, e.g., in U.S. Pat. Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, and in the following scientific publications: Marks et al., BioTechnology, 10:779-783 (1992); Lonberg et al., Nature, 368:856-859 (1994); Morrison, Nature, 368:812-13 (1994); Fishwild et al., Nature Biotechnology, 14:845-51 (1996); Neuberger, Nature Biotechnology, 14:826 (1996); Lonberg & Huszar, Inter. Rev. Immunol., 13:65-93 (1995).

In one embodiment, the antibody is conjugated to an “effector” moiety. The effector moiety can be any number of molecules, including labeling moieties such as radioactive labels or fluorescent labels, or can be a therapeutic moiety. In one aspect the antibody modulates the activity of the protein.

The nucleic acids of the differentially expressed genes of this invention or their encoded polypeptides refer to all forms of nucleic acids (e.g., gene, pre-mRNA, mRNA) or proteins, their polymorphic variants, alleles, mutants, and interspecies homologs that (as applicable to nucleic acid or protein): (1) have an amino acid sequence that has greater than about 60% amino acid sequence identity, 65%, 70%, 75%, 80%, 85%, 90%, preferably 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or greater amino acid sequence identity, preferably over a region of at least about 25, 50, 100, 200, 500, 1000, or more amino acids, to a polypeptide encoded by a referenced nucleic acid or an amino acid sequence described herein; (2) specifically bind to antibodies, e.g., polyclonal antibodies, raised against an immunogen comprising a referenced amino acid sequence, immunogenic fragments thereof, and conservatively modified variants thereof; (3) specifically hybridize under stringent hybridization conditions to a nucleic acid encoding a referenced amino acid sequence, and conservatively modified variants thereof; (4) have a nucleic acid sequence that has greater than about 95%, preferably greater than about 96%, 97%, 98%, 99%, or higher nucleotide sequence identity, preferably over a region of at least about 25, 50, 100, 200, 500, 1000, or more nucleotides, to a reference nucleic acid sequence. A polynucleotide or polypeptide sequence is typically from a mammal including, but not limited to, primate, e.g., human; rodent, e.g., rat, mouse, hamster; cow, pig, horse, sheep, or any mammal. The nucleic acids and proteins of the invention include both naturally occurring or recombinant molecules. Truncated and alternatively spliced forms of these antigens are included in the definition.

The phrase “specifically (or selectively) binds” when referring to a protein, nucleic acid, antibody, or small molecule compound refers to a binding reaction that is determinative of the presence of the protein or nucleic acid, such as the differentially expressed genes of the present invention, often in a heterogeneous population of proteins or nucleic acids and other biologics. In the case of antibodies, under designated immunoassay conditions, a specified antibody may bind to a particular protein at least two times the background and more typically more than 10 to 100 times background. Specific binding to an antibody under such conditions requires an antibody that is selected for its specificity for a particular protein. For example, polyclonal antibodies can be selected to obtain only those polyclonal antibodies that are specifically immunoreactive with the selected antigen and not with other proteins. This selection may be achieved by subtracting out antibodies that cross-react with other molecules. A variety of immunoassay formats may be used to select antibodies specifically immunoreactive with a particular protein. For example, solid-phase ELISA immunoassays are routinely used to select antibodies specifically immunoreactive with a protein (see, e.g., Harlow & Lane, Antibodies, A Laboratory Manual (1988) for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity).

The phrase “functional effects” in the context of assays for testing compounds that modulate a marker protein includes the determination of a parameter that is indirectly or directly under the influence of a biomarker of the invention, e.g., a chemical or phenotypic effect such as altered chemokine cell signaling. A functional effect therefore includes ligand binding activity, transcriptional activation or repression, the ability of cells to proliferate, the ability to migrate, among others. “Functional effects” include in vitro, in vivo, and ex vivo activities.

By “determining the functional effect” is meant assaying for a compound that increases or decreases a parameter that is indirectly or directly under the influence of a biomarker of the invention, e.g., measuring physical and chemical or phenotypic effects. Such functional effects can be measured by any means known to those skilled in the art, e.g., changes in spectroscopic characteristics (e.g., fluorescence, absorbance, refractive index); hydrodynamic (e.g., shape), chromatographic; or solubility properties for the protein; ligand binding assays, e.g., binding to antibodies; measuring inducible markers or transcriptional activation of the marker; measuring changes in enzymatic activity; the ability to increase or decrease cellular proliferation, apoptosis, cell cycle arrest, measuring changes in cell surface markers. The functional effects can be evaluated by many means known to those skilled in the art, e.g., microscopy for quantitative or qualitative measures of alterations in morphological features, measurement of changes in RNA or protein levels for other genes expressed in chemokine-responsive cells, measurement of RNA stability, identification of downstream or reporter gene expression (CAT, luciferase, β-gal, GFP and the like), e.g., via chemiluminescence, fluorescence, colorimetric reactions, antibody binding, inducible markers, etc.

“Inhibitors,” “activators,” and “modulators” of the markers are used to refer to activating, inhibitory, or modulating molecules identified using in vitro and in vivo assays of biomarkers responsive to IVIG treatment of relapsing-remitting multiple sclerosis (RRMS). Inhibitors are compounds that, e.g., bind to, partially or totally block activity, decrease, prevent, delay activation, inactivate, desensitize, or down regulate the activity or expression of biomarkers responsive to IVIG treatment of relapsing-remitting multiple sclerosis (RRMS). “Activators” are compounds that increase, open, activate, facilitate, enhance activation, sensitize, agonize, or up regulate activity of biomarkers responsive to IVIG treatment of relapsing-remitting multiple sclerosis (RRMS), e.g., agonists. Inhibitors, activators, or modulators also include genetically modified versions of biomarkers responsive to IVIG treatment of relapsing-remitting multiple sclerosis (RRMS), e.g., versions with altered activity, as well as naturally occurring and synthetic ligands, antagonists, agonists, antibodies, peptides, cyclic peptides, nucleic acids, antisense molecules, ribozymes, RNAi molecules, small organic molecules and the like. Such assays for inhibitors and activators include, e.g., expressing biomarkers responsive to IVIG treatment of relapsing-remitting multiple sclerosis (RRMS) in vitro, in cells, or cell extracts, applying putative modulator compounds, and then determining the functional effects on activity, as described above.

Samples or assays comprising biomarkers responsive to IVIG treatment of relapsing-remitting multiple sclerosis (RRMS) that are treated with a potential activator, inhibitor, or modulator are compared to control samples without the inhibitor, activator, or modulator to examine the extent of inhibition. Control samples (untreated with inhibitors) are assigned a relative protein activity value of 100%. Inhibition of biomarkers responsive to IVIG treatment of relapsing-remitting multiple sclerosis (RRMS) is achieved when the activity value relative to the control is about 80%, preferably 50%, more preferably 25-0%. Activation of biomarkers responsive to IVIG treatment of relapsing-remitting multiple sclerosis (RRMS) is achieved when the activity value relative to the control (untreated with activators) is 110%, more preferably 150%, more preferably 200-500% (i.e., two to five fold higher relative to the control), more preferably 1000-3000% higher.

The term “test compound” or “drug candidate” or “modulator” or grammatical equivalents as used herein describes any molecule, either naturally occurring or synthetic, e.g., protein, oligopeptide (e.g., from about 5 to about 25 amino acids in length, preferably from about 10 to 20 or 12 to 18 amino acids in length, preferably 12, 15, or 18 amino acids in length), small organic molecule, polysaccharide, peptide, circular peptide, lipid, fatty acid, siRNA, polynucleotide, oligonucleotide, etc., to be tested for the capacity to directly or indirectly modulate biomarkers responsive to IVIG treatment of relapsing-remitting multiple sclerosis (RRMS). The test compound can be in the form of a library of test compounds, such as a combinatorial or randomized library that provides a sufficient range of diversity. Test compounds are optionally linked to a fusion partner, e.g., targeting compounds, rescue compounds, dimerization compounds, stabilizing compounds, addressable compounds, and other functional moieties. Conventionally, new chemical entities with useful properties are generated by identifying a test compound (called a “lead compound”) with some desirable property or activity, e.g., inhibiting activity, creating variants of the lead compound, and evaluating the property and activity of those variant compounds. Often, high throughput screening (HTS) methods are employed for such an analysis.

A “small organic molecule” refers to an organic molecule, either naturally occurring or synthetic, that has a molecular weight of more than about 50 daltons and less than about 2500 daltons, preferably less than about 2000 daltons, preferably between about 100 to about 1000 daltons, more preferably between about 200 to about 500 daltons.

Prognostic Methods

The present invention provides methods of providing a prognosis of IVIG treatment of multiple sclerosis, including relapsing-remitting multiple sclerosis (RRMS), Alzheimer's disease, or Parkinson's disease by detecting the expression of markers overexpressed or underexpressed in patients treated with IVIG. Providing a prognosis involves determining the level of one or more IVIG responsive biomarker polynucleotides or the corresponding polypeptides in a patient or patient sample and then comparing the level to a baseline or range. Typically, the baseline value is representative of levels of the polynucleotide or nucleic acid in a relapsing-remitting multiple sclerosis (RRMS) patient prior to IVIG treatment, as measured using a biological sample such as a sample of a bodily fluid (e.g., blood or cerebrospinal fluid). Variation of levels of a polynucleotide or corresponding polypeptides of the invention from the baseline range (either up or down) indicates that the patient is benefiting from IVIG treatment of relapsing-remitting multiple sclerosis (RRMS).

As used herein, the term “providing a prognosis” refers to providing a prediction of the probable course and outcome of treatment of a patient suffering from multiple sclerosis, including relapsing-remitting multiple sclerosis (RRMS), Alzheimer's disease, or Parkinson's disease with IVIG. The methods can also be used to devise a suitable alternative or additional therapy for multiple sclerosis, including relapsing-remitting multiple sclerosis (RRMS) treatment, Alzheimer's disease, or Parkinson's disease, e.g., by indicating the failure of IVIG treatment to alleviate multiple sclerosis, including relapsing-remitting multiple sclerosis (RRMS), Alzheimer's disease, or Parkinson's disease. The prognosis can be used to adjust dose or frequency of IVIG administration as well.

Antibody reagents can be used in assays to detect expression levels of the biomarkers of the invention in patient samples using any of a number of immunoassays known to those skilled in the art. Immunoassay techniques and protocols are generally described in Price and Newman, “Principles and Practice of Immunoassay,” 2nd Edition, Grove's Dictionaries, 1997; and Gosling, “Immunoassays: A Practical Approach,” Oxford University Press, 2000. A variety of immunoassay techniques, including competitive and non-competitive immunoassays, can be used. See, e.g., Self et al., Curr. Opin. Biotechnol., 7:60-65 (1996). The term immunoassay encompasses techniques including, without limitation, enzyme immunoassays (EIA) such as enzyme multiplied immunoassay technique (EMIT), enzyme-linked immunosorbent assay (ELISA), IgM antibody capture ELISA (MAC ELISA), and microparticle enzyme immunoassay (MEIA); capillary electrophoresis immunoassays (CEIA); radioimmunoassays (RIA); immunoradiometric assays (IRMA); fluorescence polarization immunoassays (FPIA); and chemiluminescence assays (CL). If desired, such immunoassays can be automated. Immunoassays can also be used in conjunction with laser induced fluorescence. See, e.g., Schmalzing et al., Electrophoresis, 18:2184-93 (1997); Bao, J. Chromatogr. B. Biomed. Sci., 699:463-80 (1997). Liposome immunoassays, such as flow-injection liposome immunoassays and liposome immunosensors, are also suitable for use in the present invention. See, e.g., Rongen et al., J. Immunol. Methods, 204:105-133 (1997). In addition, nephelometry assays, in which the formation of protein/antibody complexes results in increased light scatter that is converted to a peak rate signal as a function of the marker concentration, are suitable for use in the methods of the present invention. Nephelometry assays are commercially available from Beckman Coulter (Brea, Calif.; Kit #449430) and can be performed using a Behring Nephelometer Analyzer (Fink et al., J. Clin. Chem. Clin. Biochem., 27:261-276 (1989)).

Specific immunological binding of antibodies can be detected directly or indirectly. Direct labels include fluorescent or luminescent tags, metals, dyes, radionuclides, and the like, attached to the antibody. An antibody labeled with iodine-125 (¹²⁵I) can be used. A chemiluminescence assay using a chemiluminescent antibody specific for the nucleic acid is suitable for sensitive, non-radioactive detection of protein levels. An antibody labeled with fluorochrome is also suitable. Examples of fluorochromes include, without limitation, DAPI, fluorescein, Hoechst 33258, R-phycocyanin, B-phycoerythrin, R-phycoerythrin, rhodamine, Texas red, and lissamine. Indirect labels include various enzymes well known in the art, such as horseradish peroxidase (HRP), alkaline phosphatase (AP), β-galactosidase, urease, and the like. A horseradish-peroxidase detection system can be used, for example, with the chromogenic substrate tetramethylbenzidine (TMB), which yields a soluble product in the presence of hydrogen peroxide that is detectable at 450 nm. An alkaline phosphatase detection system can be used with the chromogenic substrate p-nitrophenyl phosphate, for example, which yields a soluble product readily detectable at 405 nm. Similarly, a β-galactosidase detection system can be used with the chromogenic substrate o-nitrophenyl-β-D-galactopyranoside (ONPG), which yields a soluble product detectable at 410 nm. An urease detection system can be used with a substrate such as urea-bromocresol purple (Sigma Immunochemicals; St. Louis, Mo.).

A signal from the direct or indirect label can be analyzed, for example, using a spectrophotometer to detect color from a chromogenic substrate; a radiation counter to detect radiation such as a gamma counter for detection of ¹²⁵I; or a fluorometer to detect fluorescence in the presence of light of a certain wavelength. For detection of enzyme-linked antibodies, a quantitative analysis can be made using a spectrophotometer such as an EMAX Microplate Reader (Molecular Devices; Menlo Park, Calif.) in accordance with the manufacturer's instructions. If desired, the assays of the present invention can be automated or performed robotically, and the signal from multiple samples can be detected simultaneously.

The antibodies can be immobilized onto a variety of solid supports, such as magnetic or chromatographic matrix particles, the surface of an assay plate (e.g., microtiter wells), pieces of a solid substrate material or membrane (e.g., plastic, nylon, paper), and the like. An assay strip can be prepared by coating the antibody or a plurality of antibodies in an array on a solid support. This strip can then be dipped into the test sample and processed quickly through washes and detection steps to generate a measurable signal, such as a colored spot.

Alternatively, nucleic acid binding molecules such as probes, oligonucleotides, oligonucleotide arrays, and primers can be used in assays to detect differential RNA expression in patient samples, e.g., RT-PCR. In one embodiment, RT-PCR is used according to standard methods known in the art. In another embodiment, PCR assays such as Taqman® assays available from, e.g., Applied Biosystems, can be used to detect nucleic acids and variants thereof. In other embodiments, qPCR and nucleic acid microarrays can be used to detect nucleic acids. Reagents that bind to selected biomarkers can be prepared according to methods known to those of skill in the art or purchased commercially.

Analysis of nucleic acids can be achieved using routine techniques such as Southern analysis, reverse-transcriptase polymerase chain reaction (RT-PCR), or any other methods based on hybridization to a nucleic acid sequence that is complementary to a portion of the marker coding sequence (e.g., slot blot hybridization) are also within the scope of the present invention. Applicable PCR amplification techniques are described in, e.g., Ausubel et al. and Innis et al., supra. General nucleic acid hybridization methods are described in Anderson, “Nucleic Acid Hybridization,” BIOS Scientific Publishers, 1999. Amplification or hybridization of a plurality of nucleic acid sequences (e.g., genomic DNA, mRNA or cDNA) can also be performed from mRNA or cDNA sequences arranged in a microarray. Microarray methods are generally described in Hardiman, “Microarrays Methods and Applications: Nuts & Bolts,” DNA Press, 2003; and Baldi et al., “DNA Microarrays and Gene Expression From Experiments to Data Analysis and Modeling,” Cambridge University Press, 2002.

Analysis of nucleic acid markers and their variants can be performed using techniques known in the art including, without limitation, microarrays, polymerase chain reaction (PCR)-based analysis, sequence analysis, and electrophoretic analysis. A non-limiting example of a PCR-based analysis includes a Taqman® allelic discrimination assay available from Applied Biosystems. Non-limiting examples of sequence analysis include Maxam-Gilbert sequencing, Sanger sequencing, capillary array DNA sequencing, thermal cycle sequencing (Sears et al., Biotechniques, 13:626-633 (1992)), solid-phase sequencing (Zimmerman et al., Methods Mol. Cell Biol., 3:39-42 (1992)), sequencing with mass spectrometry such as matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS; Fu et al., Nat. Biotechnol., 16:381-384 (1998)), and sequencing by hybridization. Chee et al., Science, 274:610-614 (1996); Drmanac et al., Science, 260:1649-1652 (1993); Drmanac et al., Nat. Biotechnol., 16:54-58 (1998). Non-limiting examples of electrophoretic analysis include slab gel electrophoresis such as agarose or polyacrylamide gel electrophoresis, capillary electrophoresis, and denaturing gradient gel electrophoresis. Other methods for detecting nucleic acid variants include, e.g., the INVADER® assay from Third Wave Technologies, Inc., restriction fragment length polymorphism (RFLP) analysis, allele-specific oligonucleotide hybridization, a heteroduplex mobility assay, single strand conformational polymorphism (SSCP) analysis, single-nucleotide primer extension (SNUPE) and pyrosequencing.

A detectable moiety can be used in the assays described herein. A wide variety of detectable moieties can be used, with the choice of label depending on the sensitivity required, ease of conjugation with the antibody, stability requirements, and available instrumentation and disposal provisions. Suitable detectable moieties include, but are not limited to, radionuclides, fluorescent dyes (e.g., fluorescein, fluorescein isothiocyanate (FITC), Oregon Green™, rhodamine, Texas red, tetrarhodimine isothiocynate (TRITC), Cy3, Cy5, etc.), fluorescent markers (e.g., green fluorescent protein (GFP), phycoerythrin, etc.), autoquenched fluorescent compounds that are activated by tumor-associated proteases, enzymes (e.g., luciferase, horseradish peroxidase, alkaline phosphatase, etc.), nanoparticles, biotin, digoxigenin, and the like.

Useful physical formats comprise surfaces having a plurality of discrete, addressable locations for the detection of a plurality of different markers. Such formats include microarrays and certain capillary devices. See, e.g., Ng et al., J. Cell Mol. Med., 6:329-340 (2002); U.S. Pat. No. 6,019,944. In these embodiments, each discrete surface location may comprise antibodies to immobilize one or more markers for detection at each location. Surfaces may alternatively comprise one or more discrete particles (e.g., microparticles or nanoparticles) immobilized at discrete locations of a surface, where the microparticles comprise antibodies to immobilize one or more markers for detection.

Analysis can be carried out in a variety of physical formats. For example, the use of microtiter plates or automation could be used to facilitate the processing of large numbers of test samples. Alternatively, single sample formats could be developed to facilitate a prognosis in a timely fashion.

Alternatively, the antibodies or nucleic acid probes of the invention can be applied to sections of patient biopsies immobilized on microscope slides. The resulting antibody staining or in situ hybridization pattern can be visualized using any one of a variety of light or fluorescent microscopic methods known in the art.

In another format, the various markers of the invention also provide reagents for in vivo imaging such as, for instance, the imaging of labeled regents that detect the nucleic acids or encoded proteins of the biomarkers of the invention. For in vivo imaging purposes, reagents that detect the presence of proteins encoded by IVIG-responsive relapsing-remitting multiple sclerosis (RRMS) biomarkers, such as antibodies, may be labeled using an appropriate marker, such as a fluorescent marker.

Preparations and Administration of IVIG

IVIG compositions comprising whole antibodies have been described for the treatment of certain autoimmune conditions. (See, e.g., U.S. Patent Publication US 2002/0114802, US 2003/0099635, and US 2002/0098182.) The IVIG compositions disclosed in these references include polyclonal antibodies.

Immunoglobulin preparations according to the present invention can be prepared from any suitable starting materials. For example, immunoglobulin preparations can be prepared from donor serum or monoclonal or recombinant immunoglobulins. In a typical example, blood is collected from healthy donors. Usually, the blood is collected from the same species of animal as the subject to which the immunoglobulin preparation will be administered (typically referred to as “homologous” immunoglobulins). The immunoglobulins are isolated from the blood by suitable procedures, such as, for example, Cohn fractionation, ultracentrifugation, electrophoretic preparation, ion exchange chromatography, affinity chromatography, immunoaffinity chromatography, polyethylene glycol fractionation, or the like. (See, e.g., Cohn et al., J. Am. Chem. Soc. 68:459-75 (1946); Oncley et al., J. Am. Chem. Soc. 71:541-50 (1949); Barundern et al., Vox Sang. 7:157-74 (1962); Koblet et al., Vox Sang. 13:93-102 (1967); U.S. Pat. Nos. 5,122,373 and 5,177,194; the disclosures of which are incorporated by reference herein.)

In certain embodiments, immunoglobulin is prepared from gamma globulin-containing products produced by the alcohol fractionation and/or ion exchange and affinity chromatography methods well known to those skilled in the art. Purified Cohn Fraction II is commonly used. The starting Cohn Fraction II paste is typically about 95 percent IgG and is comprised of the four IgG subtypes. The different subtypes are present in Fraction II in approximately the same ratio as they are found in the pooled human plasma from which they are obtained. The Fraction II is further purified before formulation into an administrable product. For example, the Fraction II paste can be dissolved in a cold purified aqueous alcohol solution and impurities removed via precipitation and filtration. Following the final filtration, the immunoglobulin suspension can be dialyzed or diafiltered (e.g., using ultrafiltration membranes having a nominal molecular weight limit of less than or equal to 100,000 daltons) to remove the alcohol. The solution can be concentrated or diluted to obtain the desired protein concentration and can be further purified by techniques well known to those skilled in the art.

Preparative steps can be used to enrich a particular isotype or subtype of immunoglobulin. For example, protein A, protein G or protein H sepharose chromatography can be used to enrich a mixture of immunoglobulins for IgG, or for specific IgG subtypes. (See generally Harlow and Lane, Using Antibodies, Cold Spring Harbor Laboratory Press (1999); Harlow and Lane, Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory Press (1988); U.S. Pat. No. 5,180,810.)

Commercial sources of immunoglobulins can also be used. Such sources include but are not limited to: Gammagard S/D® (Baxter Healthcare); BayRho-D® products (Bayer Biological); Gamimune N®, 5% (Bayer Biological); Gamimune N®, 5% Solvent/Detergent Treated (Bayer Biological); Gamimune N®, 10% (Bayer Biological); Sandoglobulin I.V.® (Novartis); Polygam S/D® (American Red Cross); Venoglobulin-S® 5% Solution Solvent Detergent Treated (Alpha Therapeutic); Venoglobulin-S® 10% Solution Solvent Detergent/Treated (Alpha Therapeutic); and VZIG® (American Red Cross). The commercial source of immunoglobulin preparation for use in the methods of the present invention is not critical.

An alternative approach is to use fragments of antibodies, such as Fc fragments of immunoglobulins. An Fc preparation comprises Fc fragments of immunoglobulins. The term “Fc fragment” refers to a portion of an immunoglobulin heavy chain constant region containing at least one heavy chain constant region domain (e.g., C_(H)2, C_(H)3 and/or C_(H)4) or an antigenic portion thereof, but excluding the variable regions of the immunoglobulin. (As used herein, a variable region refers to region of the immunoglobulin that binds to an antigen, but excludes the C_(H)1 and C_(L) domains.) The Fc preparation can contain entire Fc fragments and/or portions thereof (e.g., one or more heavy chain constant region domains or portions thereof containing an epitope(s) bound by the rheumatoid factors). An Fc fragment optionally can include an immunoglobulin hinge region, a heavy chain C_(H)1 domain, and/or a heavy chain C_(H)1 domain joined to a light chain C_(L) domain.

An Fc preparation includes Fc fragments of at least one Fc isotype and can contain a mixture of immunoglobulin Fc fragments of different isotypes (e.g., IgA, IgD, IgE, IgG and/or IgM). The Fc preparation also can contain predominantly (at least 60%, at least 75%, at least 90%, at least 95%, or at least 99%) Fc fragments from one immunoglobulin isotype, and can contain minor amounts of the other subtypes. For example, an Fc preparation can contain at least at least about 75%, at least about 90%, at least about 95%, or at least about 99% IgG Fc fragments. In addition, the Fc preparation can comprise a single IgG subtype or a mixture two or more of IgG Fc subtypes. Suitable IgG subtypes include IgG1, IgG2, IgG3, and IgG4. In a specific embodiment, the Fc preparation comprises IgG1 Fc fragments.

An Fc preparation is substantially free of F(ab′)₂ fragments (i.e., heavy and light chain variable and first constant regions and a portion of the hinge region, which can be produced by pepsin digestion of the antibody molecule), Fab′ fragments (i.e., Fab′ fragments which can be generated by reducing the disulfide bridges of the F(ab′)₂ fragment), or Fab fragments (i.e., which can be generated by treating the antibody molecule with papain and a reducing agent). In this context, “substantially free” means the Fc preparation contains less than about 30%, less than about 20%, less than about 10%, less than about 5%, or less than about 1% F(ab′)₂, Fab′ or Fab fragments. In another embodiment, the Fc preparation contains Fc fragments which are essentially free of F(ab′)₂, Fab′ or Fab fragments. The Fc preparations are typically substantially free of whole (i.e., full length) immunoglobulins. In this context, “substantially free” means less than about 25%, or less than about 10%, or less than about 5%, or less than about 2%, less than about 1% or are free of full length immunoglobulins.

Immunoglobulins can be cleaved at any suitable time during preparation to separate the Fc fragments from the Fab, F(ab′) and/or F(ab′)₂ fragments, as applicable. A suitable enzyme for cleavage is, for example, papain, pepsin or plasmin. (See, e.g., Harlow and Lane, Using Antibodies, Cold Spring Harbor Laboratory Press (1999); Plan and Makula, Vox Sanguinis 28:157-75 (1975).) After cleavage, the Fc portions can be separated from the Fab F(ab′) and/or F(ab′)₂ fragments by, for example, affinity chromatography, ion exchange chromatography, gel filtration, or the like. In a specific example, immunoglobulins are digested with papain to separate the Fc fragment from the Fab fragments. The digestion mixture is then subjected to cationic exchange chromatography to separate the Fc fragments from the Fab fragments.

Immunoglobulin or Fc fragments can also be prepared from hybridomas or other culture system which express monoclonal antibody. (See, e.g., Kohler and Milstein, Nature 256:495-97 (1975); Hagiwara and Yuasa, Hum. Antibodies Hybridomas 4:15-19 (1993); Kozbor et al., Immunology Today 4:72 (1983); Cole et al., in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp. 77-96 (1985).) Human monoclonal antibodies can be obtained, for example, from human hybridomas (see, e.g., Cote et al., Proc. Natl. Acad. Sci. USA 80:2026-30 (1983)) or by transforming human B cells with EBV virus in vitro (see, e.g., Cole et al., supra). Monoclonal antibodies produced from hybridomas can be purified and the Fc fragments separated from the Fab, F(ab′) and/or F(ab)₂ fragments as described herein or as known to the skilled artisan.

Immunoglobulin or Fc fragments also can be produced recombinantly, such as from eukaryotic cell culture systems. For example, an Fc fragment of an immunoglobulin can be recombinantly produced by Chinese hamster ovary (CHO) cells transfected with a vector containing a DNA sequence encoding the Fc fragment. Methods for creating such recombinant mammalian cells are described in, for example, Sambrook and Russell, Molecular Cloning, A Laboratory Manual, 3rd ed. (Cold Spring Harbor Laboratory Press (New York) 2001) and Ausubel et al., Short Protocols in Molecular Biology, 4th ed. (John Wiley & Sons, Inc. (New York) 1999) and are known to the skilled artisan. Recombinant Fc can also be produced in other mammalian cell lines, such as baby hamster kidney (BHK) cells. Methods of culturing recombinant cells to produce recombinant proteins are also known to the art.

A variety of other expression systems can be utilized to express recombinant immunoglobulins or Fc fragments. These include, but are not limited to, insect cell systems and microorganisms such as yeast or bacteria which have been transfected or transformed with an expression cassette encoding the desired Fc fragment. In certain embodiments, the microorganism optionally can be engineered to reproduce glycosylation patterns of mammalian or human Fc fragments.

In certain embodiments, further preparative steps can be used in order to render an immunoglobulin or Fc preparation safe for use in the methods according to the present invention. Such steps can include, for example, treatment with solvent/detergent, pasteurization and sterilization. Additional preparative steps may be used in order to ensure the safety of an Fc preparation. Such preparative steps can include, for example, enzymatic hydrolysis, chemical modification via reduction and alkylation, sulfonation, treatment with β-propiolactone, treatment at low pH, or the like. Descriptions of suitable methods can also be found in, for example, U.S. Pat. Nos. 4,608,254; 4,687,664; 4,640,834; 4,814,277; 5,864,016; 5,639,730 and 5,770,199; Romer et al., Vox Sang. 42:62-73 (1982); Romer et al., Vox Sang. 42:74-80 (1990); and Rutter, J. Neurosurg. Psychiat. 57 (Suppl.):2-5 (1994) (the disclosures of which are incorporated by reference herein).

An effective amount of an immunoglobulin or Fc preparation is administered to the subject generally by intravenous means. The term “effective amount” refers to an amount of an immunoglobulin or Fc preparation that results in an improvement or remediation of RRMS in the subject. An effective amount to be administered to the subject can be determined by a physician with consideration of individual differences in age, weight, disease severity and response to the therapy. In certain embodiments, an immunoglobulin or Fc preparation can be administered to a subject at about 5 mg/kilogram to about 500 mg/kilogram each day. In additional embodiments, an mmunoglobulin or Fc preparation can be administered in amounts of at least about 10 mg/kilogram, at last 15 mg/kilogram, at least 20 mg/kilogram, at least 25 mg/kilogram, at least 30 mg/kilogram or at least 50 mg/kilogram. In additional embodiments, an mmunoglobulin or Fc preparation can be administered to a subject at doses up to about 100 mg/kilogram, to about 150 mg/kilogram, to about 200 mg/kilogram, to about 250 mg/kilogram, to about 300 mg/kilogram, to about 400 mg/kilogram each day. In other embodiments, the doses of the mmunoglobulin or Fc preparation can be greater or less. Immunoglobulin or Fc preparations can be administered in one or more doses per day.

In accordance with the present invention, the time needed to complete a course of the treatment can be determined by a physician and may range from as short as one day to more than a month. In certain embodiments, a course of treatment can be from 1 to 6 months.

Compositions, Kits and Integrated Systems

The invention provides compositions, kits and integrated systems for practicing the assays described herein using antibodies specific for the polypeptides or nucleic acids specific for the polynucleotides of the invention.

Kits for carrying out the diagnostic assays of the invention typically include a probe that comprises an antibody or nucleic acid sequence that specifically binds to polypeptides or polynucleotides of the invention, and a label for detecting the presence of the probe. The kits may include several antibodies or polynucleotide sequences encoding polypeptides of the invention, e.g., a cocktail of antibodies that recognize the proteins encoded by the biomarkers of the invention.

Methods to Identify Compounds

A variety of methods may be used to identify compounds that prevent or treat multiple sclerosis, including relapsing-remitting multiple sclerosis (RRMS), Alzheimer's disease, or Parkinson's disease. Typically, an assay that provides a readily measured parameter is adapted to be performed in the wells of multi-well plates in order to facilitate the screening of members of a library of test compounds as described herein. Thus, in one embodiment, an appropriate number of cells, e.g., T cells, can be plated into the cells of a multi-well plate, and the effect of a test compound on the expression of an IVIG-responsive relapsing-remitting multiple sclerosis (RRMS) biomarker can be determined.

The compounds to be tested can be any small chemical compound, or a macromolecule, such as a protein, sugar, nucleic acid or lipid. Typically, test compounds will be small chemical molecules and peptides. Essentially any chemical compound can be used as a test compound in this aspect of the invention, although most often compounds that can be dissolved in aqueous or organic (especially DMSO-based) solutions are used. The assays are designed to screen large chemical libraries by automating the assay steps and providing compounds from any convenient source to assays, which are typically run in parallel (e.g., in microtiter formats on microtiter plates in robotic assays). It will be appreciated that there are many suppliers of chemical compounds, including Sigma (St. Louis, Mo.), Aldrich (St. Louis, Mo.), Sigma-Aldrich (St. Louis, Mo.), Fluka Chemika-Biochemica Analytika (Buchs Switzerland) and the like.

In one preferred embodiment, high throughput screening methods are used which involve providing a combinatorial chemical or peptide library containing a large number of potential therapeutic compounds. Such “combinatorial chemical libraries” or “ligand libraries” are then screened in one or more assays, as described herein, to identify those library members (particular chemical species or subclasses) that display a desired characteristic activity. In this instance, such compounds are screened for their ability to reduce or increase the expression of the relapsing-remitting multiple sclerosis (RRMS) biomarkers of the invention.

A combinatorial chemical library is a collection of diverse chemical compounds generated by either chemical synthesis or biological synthesis, by combining a number of chemical “building blocks” such as reagents. For example, a linear combinatorial chemical library such as a polypeptide library is formed by combining a set of chemical building blocks (amino acids) in every possible way for a given compound length (i.e., the number of amino acids in a polypeptide compound). Millions of chemical compounds can be synthesized through such combinatorial mixing of chemical building blocks.

Preparation and screening of combinatorial chemical libraries are well known to those of skill in the art. Such combinatorial chemical libraries include, but are not limited to, peptide libraries (see, e.g., U.S. Pat. No. 5,010,175, Furka, Int. J. Pept. Prot. Res., 37:487-493 (1991) and Houghton et al., Nature, 354:84-88 (1991)). Other chemistries for generating chemical diversity libraries can also be used. Such chemistries include, but are not limited to: peptoids (e.g., PCT Publication No. WO 91/19735), encoded peptides (e.g., PCT Publication No. WO 93/20242), random bio-oligomers (e.g., PCT Publication No. WO 92/00091), benzodiazepines (e.g., U.S. Pat. No. 5,288,514), diversomers such as hydantoins, benzodiazepines and dipeptides (Hobbs et al., PNAS USA, 90:6909-6913 (1993)), vinylogous polypeptides (Hagihara et al., J. Amer. Chem. Soc., 114:6568 (1992)), nonpeptidal peptidomimetics with glucose scaffolding (Hirschmann et al., J. Amer. Chem. Soc., 114:9217-9218 (1992)), analogous organic syntheses of small compound libraries (Chen et al., J. Amer. Chem. Soc., 116:2661 (1994)), oligocarbamates (Cho et al., Science, 261:1303 (1993)), and/or peptidyl phosphonates (Campbell et al., J. Org. Chem., 59:658 (1994)), nucleic acid libraries (see Ausubel, Berger and Sambrook, all supra), peptide nucleic acid libraries (see, e.g., U.S. Pat. No. 5,539,083), antibody libraries (see, e.g., Vaughn et al., Nature Biotechnology, 14(3):309-314 (1996) and PCT/US96/10287), carbohydrate libraries (see, e.g., Liang et al., Science, 274:1520-1522 (1996) and U.S. Pat. No. 5,593,853), small organic molecule libraries (see, e.g., benzodiazepines, Baum C&EN, January 18, page 33 (1993); isoprenoids, U.S. Pat. No. 5,569,588; thiazolidinones and metathiazanones, U.S. Pat. No. 5,549,974; pyrrolidines, U.S. Pat. Nos. 5,525,735 and 5,519,134; morpholino compounds, U.S. Pat. No. 5,506,337; benzodiazepines, U.S. Pat. No. 5,288,514, and the like).

Devices for the preparation of combinatorial libraries are commercially available (see, e.g., 357 MPS, 390 MPS, Advanced Chem Tech, Louisville Ky., Symphony, Rainin, Woburn, Mass., 433A Applied Biosystems, Foster City, Calif., 9050 Plus, Millipore, Bedford, Mass.). In addition, numerous combinatorial libraries are themselves commercially available (see, e.g., ComGenex, Princeton, N.J., Asinex, Moscow, Ru, Tripos, Inc., St. Louis, Mo., ChemStar, Ltd, Moscow, RU, 3D Pharmaceuticals, Exton, Pa., Martek Biosciences, Columbia, Md., etc.).

In the high throughput assays of the invention, it is possible to screen up to several thousand different modulators or ligands in a single day. In particular, each well of a microtiter plate can be used to run a separate assay against a selected potential modulator, or, if concentration or incubation time effects are to be observed, every 5-10 wells can test a single modulator. Thus, a single standard microtiter plate can assay about 96 modulators. If 1536 well plates are used, then a single plate can easily assay from about 100- about 1500 different compounds. It is possible to assay many plates per day; assay screens for up to about 6,000, 20,000, 50,000, or 100,000 or more different compounds is possible using the integrated systems of the invention.

Methods to Inhibit or Activate Biomarker Proteins or Biomarker Receptor Function Using Antibodies

Because the biomarkers of the present invention are overexpressed or underexpressed in response to IVIG treatment of multiple sclerosis, Alzheimer's disease, or Parkinson's disease, the biomarker proteins or their cellular receptors, may serve as targets for multiple sclerosis therapy using antibodies. In the case of, for instance, of chemokines, such as CXCL5, CXCL3, and CCL13, whose expression is decreased upon treatment of RRMS with IVIG, antibodies that bind to and inactivate these chemokines or their receptors can be used in the treatment of multiple sclerosis, Alzheimer's disease, or Parkinson's disease. Alternatively, in the case of chemokines, such as XCL2, whose expression is increased upon IVIG treatment, antibodies may be generated which bind to and activate XCL2 receptors, thus mimicking the effect of XCL2 binding.

The antibodies described above may be formulated into pharmaceutical compositions comprising a carrier suitable for the desired delivery method. Suitable carriers include any material which when combined with the antibody does not interfere with function of the antibody and is non-reactive with the subject's immune systems. Examples include, but are not limited to, any of a number of standard pharmaceutical carriers such as sterile phosphate buffered saline solutions, bacteriostatic water, and the like (see, generally, Remington's Pharmaceutical Sciences, 20^(th) ed., 2003).

Antibody formulations may be administered via any route capable of delivering the antibodies to an individual suffering from multiple sclerosis. Potentially effective routes of administration include, but are not limited to, intravenous, intraperitoneal, intramuscular, intradermal, and the like. One preferred route of administration is by intravenous injection. A preferred formulation for intravenous injection comprises the antibodies in a solution of preserved bacteriostatic water, sterile unpreserved water, and/or diluted in polyvinylchloride or polyethylene bags containing 0.9% sterile Sodium Chloride for Injection, USP. The antibody preparation may be lyophilized and stored as a sterile powder, preferably under vacuum, and then reconstituted in bacteriostatic water containing, for example, benzyl alcohol preservative, or in sterile water prior to injection.

Treatment will generally involve the repeated administration of antibody preparations via an acceptable route of administration such as intravenous injection (IV), at an effective dose. Dosages will depend upon various factors generally appreciated by those of skill in the art, including without limitation the type, stage, the severity, grade, or stage of multiple sclerosis, the binding affinity and half life of the antibody used, the degree of biomarker or receptor expression in the patient, the desired steady-state antibody concentration level, frequency of treatment, and the influence of any other agents used in combination with the treatment method of the invention. Typical daily doses may range from about 0.1 to 100 mg/kg. Doses in the range of 10-500 mg mAb per week may be effective and well tolerated, although even higher weekly doses may be appropriate and/or well tolerated. The principal determining factor in defining the appropriate dose is the amount of a particular antibody necessary to be therapeutically effective in a particular context. Repeated administrations may be required in order to achieve longer lasting remission in RRMS. Initial loading doses may be higher. The initial loading dose may be administered as an infusion. Periodic maintenance doses may be administered similarly, provided the initial dose is well tolerated.

Methods to Inhibit Marker Protein Expression Using Nucleic Acids

A variety of nucleic acids, such as antisense nucleic acids, siRNAs or ribozymes, may be used to inhibit the function of the markers of this invention. Ribozymes that cleave mRNA at site-specific recognition sequences can be used to destroy target mRNAs, particularly through the use of hammerhead ribozymes. Hammerhead ribozymes cleave mRNAs at locations dictated by flanking regions that form complementary base pairs with the target mRNA. Preferably, the target mRNA has the following sequence of two bases: 5′-UG-3′. The construction and production of hammerhead ribozymes is well known in the art.

Gene targeting ribozymes necessarily contain a hybridizing region complementary to two regions, each of at least 5 and preferably each 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleotides in length of a target mRNA. In addition, ribozymes possess highly specific endoribonuclease activity, which autocatalytically cleaves the target sense mRNA.

With regard to antisense, siRNA or ribozyme oligonucleotides, phosphorothioate oligonucleotides can be used. Modifications of the phosphodiester linkage as well as of the heterocycle or the sugar may provide an increase in efficiency. Phosphorothioate is used to modify the phosphodiester linkage. An N3′-P5′ phosphoramidate linkage has been described as stabilizing oligonucleotides to nucleases and increasing the binding to RNA. Peptide nucleic acid (PNA) linkage is a complete replacement of the ribose and phosphodiester backbone and is stable to nucleases, increases the binding affinity to RNA, and does not allow cleavage by RNAse H. Its basic structure is also amenable to modifications that may allow its optimization as an antisense component. With respect to modifications of the heterocycle, certain heterocycle modifications have proven to augment antisense effects without interfering with RNAse H activity. An example of such modification is C-5 thiazole modification. Finally, modification of the sugar may also be considered. 2′-O-propyl and 2′-methoxyethoxy ribose modifications stabilize oligonucleotides to nucleases in cell culture and in vivo.

Inhibitory oligonucleotides can be delivered to a cell by direct transfection or transfection and expression via an expression vector. Appropriate expression vectors include mammalian expression vectors and viral vectors, into which has been cloned an inhibitory oligonucleotide with the appropriate regulatory sequences including a promoter to result in expression of the antisense RNA in a host cell. Suitable promoters can be constitutive or development-specific promoters. Transfection delivery can be achieved by liposomal transfection reagents, known in the art (e.g., Xtreme transfection reagent, Roche, Alameda, Calif.; Lipofectamine formulations, Invitrogen, Carlsbad, Calif.). Delivery mediated by cationic liposomes, by retroviral vectors and direct delivery are efficient. Another possible delivery mode is targeting using antibody to cell surface markers for the target cells.

For transfection, a composition comprising one or more nucleic acid molecules (within or without vectors) can comprise a delivery vehicle, including liposomes, for administration to a subject, carriers and diluents and their salts, and/or can be present in pharmaceutically acceptable formulations. Methods for the delivery of nucleic acid molecules are described, for example, in Gilmore, et al., Curr Drug Delivery (2006) 3:147-5 and Patil, et al., AAPS Journal (2005) 7:E61-E77, each of which are incorporated herein by reference. Delivery of siRNA molecules is also described in several U.S. Patent Publications, including for example, 2006/0019912; 2006/0014289; 2005/0239687; 2005/0222064; and 2004/0204377, the disclosures of each of which are hereby incorporated herein by reference. Nucleic acid molecules can be administered to cells by a variety of methods known to those of skill in the art, including, but not restricted to, encapsulation in liposomes, by iontophoresis, by electroporation, or by incorporation into other vehicles, including biodegradable polymers, hydrogels, cyclodextrins (see, for example Gonzalez et al., 1999, Bioconjugate Chem., 10, 1068-1074; Wang et al., International PCT publication Nos. WO 03/47518 and WO 03/46185), poly(lactic-co-glycolic)acid (PLGA) and PLCA microspheres (see for example U.S. Pat. No. 6,447,796 and US Patent Application Publication No. 2002/130430), biodegradable nanocapsules, and bioadhesive microspheres, or by proteinaceous vectors (O'Hare and Normand, International PCT Publication No. WO 00/53722). In another embodiment, the nucleic acid molecules of the invention can also be formulated or complexed with polyethyleneimine and derivatives thereof, such as polyethyleneimine-polyethyleneglycol-N-acetylgalactosamine (PEI-PEG-GAL) or polyethyleneimine-polyethyleneglycol-tri-N-acetylgalactosamine (PEI-PEG-triGAL) derivatives.

Examples of liposomal transfection reagents of use with this invention include, for example: CellFectin, 1:1.5 (M/M) liposome formulation of the cationic lipid N,NI,NII,NIII-tetramethyl-N,NI,NII,NIII-tetrapalmit-y-spermine and dioleoyl phosphatidylethanolamine (DOPE) (GIBCO BRL); Cytofectin GSV, 2:1 (M/M) liposome formulation of a cationic lipid and DOPE (Glen Research); DOTAP (N-[1-(2,3-dioleoyloxy)-N,N,N-tri-methyl-ammoniummethylsulfate) (Boehringer Manheim); Lipofectamine, 3:1 (M/M) liposome formulation of the polycationic lipid DOSPA and the neutral lipid DOPE (GIBCO BRL); and (5) siPORT (Ambion); HiPerfect (Qiagen); X-treme GENE (Roche); RNAicarrier (Epoch Biolabs) and TransPass (New England Biolabs).

In some embodiments, antisense, siRNA, or ribozyme sequences are delivered into the cell via a mammalian expression vector. For example, mammalian expression vectors suitable for siRNA expression are commercially available, for example, from Ambion (e.g., pSilencer vectors), Austin, Tex.; Promega (e.g., GeneClip, siSTRIKE, SiLentGene), Madison, Wis.; Invitrogen, Carlsbad, Calif.; InvivoGen, San Diego, Calif.; and Imgenex, San Diego, Calif. Typically, expression vectors for transcribing siRNA molecules will have a U6 promoter.

In some embodiments, antisense, siRNA, or ribozyme sequences are delivered into cells via a viral expression vector. Viral vectors suitable for delivering such molecules to cells include adenoviral vectors, adeno-associated vectors, and retroviral vectors (including lentiviral vectors). For example, viral vectors developed for delivering and expressing siRNA oligonucleotides are commercially available from, for example, GeneDetect, Bradenton, Fla.; Ambion, Austin, Tex.; Invitrogen, Carlsbad, Calif.; Open BioSystems, Huntsville, Ala.; and Imgenex, San Diego, Calif.

EXAMPLES

The following examples are offered to illustrate, but not to limit the claimed invention.

Example 1 Methods and Materials Patients Involved in the Study

10 consecutive patients with acute MS relapse as rated on McDonald's criteria (McDonald W. I. et al., Ann Neurol, 50:121-27 (2001)) were included. The diagnosis of definite MS was based on McDonald's criteria (Kurtzke J. F., Neurology, 33:1444-1452 (1983)). The EDSS (Dastidar P. et al., Med Biol Eng Comput, 37:104-7 (1999)) and volumetric brain MRI were evaluated at baseline (at relapse immediately before treatment) and 3 weeks after completion of IVIG therapy (Elovaara I. et al., Intravenous Immunoglobulin is effective and well tolerated in the treatment of MS Relapse, Manuscript submitted). The primary outcome measure of the study was a change in the EDSS score from baseline to week 3 after the start of IVIG therapy on day 21. Secondary outcome measures were changes in the volumes of T1-, T2-, Flair- and gadolinium (Gd)-enhanced lesions, the number of Gd-enhanced lesions, and brain volumes (Elovaara I. et al., Intravenous Immunoglobulin is effective and well tolerated in the treatment of MS Relapse, Manuscript submitted; Dastidar P. et al., Med Biol Eng Comput, 37:104-7 (1999)). Patients' characteristics are listed in Table 1. Before entry into the study each patient signed a form of consent. The study was approved by the Ethics Committee of Tampere University, Tampere, Finland.

Patients who received treatment with immunosuppressants in the preceding nine months or patients who received corticosteroids in the preceding 8 weeks were excluded. All patients received 0.4 g/kg/day Endobulin (Baxter AG, Vienna, Austria) for 5 days. Clinical evaluation of the patients was done before treatment with IVIG, 1 day after completion of therapy on day 6 as well as 3 weeks after the beginning of therapy on day 21. Clinical evaluation included neurological examination, determination of the EDSS score, arm index and ambulation index. A control group of five patients received standard treatment of IVMP 100 mg/day for 3 days.

TABLE 1 Characteristics of patients included in the study IVMP Patients Characteristics IVIG Patients (controls) Number of patients 10 5 Age (years, average ± SD)  40 ± 10.6 35.3 ± 8.8  Sex (male vs female) 3 vs 7 0 vs 5 Disease duration (years, 5.6 ± 3.5 5.2 ± 3.6 average ± SD) Time current vs previous 17.6 ± 21.0  5 ± 3.2 relapse (months, average ± SD) EDSS score during remission  2.3 ± 0.95 3.2 ± 2.4 (average ± SD) EDSS score at acute relapse 3.7 ± 1.1 4.2 ± 2.0 (average ± SD)

MRI Analysis

Brain MRI examinations were done using a 1.5 Tesla MRI unit (Philips Gyroscan ACS NT Intera, Best, Netherlands) as described (Kurtzke J. F., Neurology, 33:1444-1452 (1983)). The MRI protocol included sagittal T1 localizer, axial fluid attenuated inversion recovery (FLAIR), T1 magnetization transfer contrast (MTC), T1 spin echo (SE), T2 turbo spin echo (TSE) (3 mm thick and 0 mm gap) and gadolinium-enhanced T1 MTC sequences. T1 axial SE (3 mm thick and 0 mm gap) and axial FLAIR (5 mm thick and 1 mm gap) sequences were used for volumetric analyses of plaques. Computerized semiautomatic segmentation and volumetric analyses were done using Anatomatic software operating in a Windows environment. The inter- and intra-observer variability of the volumetric results has been reported elsewhere (Dastidar P. et al., Med Biol Eng Comput, 37:104-7 (1999); Heinonen T. et al., J Med Eng Technol, 22:173-8 (1998)). The volumetric accuracy of the Anatomatic program was analyzed as described (Dastidar P. et al., Med Biol Eng Comput, 37:104-7 (1999)). Good head repositioning was controlled using the same head coil, the same anatomic locations and the same pack of images in different MRI sequences. Whole spinal cords were scanned separating into upper and lower parts. The same scanner was used for all MRI examinations.

Preparation of RNA Samples

Blood samples were obtained using Vacutainer CPTTM Cell Preparation Tubes (Becton Dickinson, Franklin Lakes, N.J.). Peripheral blood mononuclear cells (PBMC) were separated from peripheral blood within 60 min after blood sampling using density gradient (Lymphoprep, Nycomed, Roskilde, DK) centrifugation according to the manufacturer's protocol. The cells were separated into T cells and non-T cells using a mixture of non-stimulating anti-CD4+ and anti-CD8+ magnetic Dynabeads (Dynal Biotech, Oslo, N) at 4° C. Cell pellets obtained from 5×10⁶ cells were thoroughly mixed with 1 ml TRIzol (Invitrogen, Carlsbad, Calif.). Aliquots were frozen and stored at −80° C. until further processing. Total RNA was isolated according to the manufacturer's protocol. RNA pellets were dissolved in nuclease-free water (Invitrogen, Carlsbad, Calif.) and stored at −80° C.

Microarray Analysis

The HU-133A Genechip (Affymetrix, Santa Clara, Calif.) containing approximately 33,000 human genes was used. 5 μg of total RNA were transcribed, labelled and hybridized in vitro on the array according to the manufacturer's protocol (see Affymetrix.com). The quality of the RNA was checked before in vitro processing using a Bioanalyzer (Agilent Technologies, Palo Alto, Calif.).

Statistical Analysis of Gene Expression Data

Statistical analysis of gene expression data was done at the Microarray Facility Tübingen, Eberhard-Karls-University Tübingen, Germany. The Affymetrix CHP files were imported into Genespring 7.1 for statistical data analysis. The signals of each array were divided by the median of all signals of the arrays from time point zero. Subsequently, a “per-gene” normalization was done by dividing all signals of a gene by the median signal of this gene. Thus the signals of each gene start at time point zero around 1 and display values greater than 1 upon increase and vice versa. The signals were log-transformed, and fold change and p-values (Welch's t-test) (Han T. et al., BMC bioinformatics, 7:9 (2006)) were calculated for each gene in pair-wise comparisons. Probe sets with a fold change of more than 2 and a p-value of less than 0.05 were identified in volcano plots and called statistically significant.

Real Time Polymerase Chain Reaction

The gene expression data obtained by microarray analysis for four representative genes were confirmed by quantitative real-time polymerase chain reaction (PCR). For this purpose, 1 μg of total T cell RNA was used for reverse transcription into cDNA according to the manufacturer's protocol (MBI Fermentas, Burlington, Canada). For each sample to be analyzed, 100 mg cDNA were dissolved in 5 μl nuclease-free water (Invitrogen, Carlsbad, Calif.) and quantitatively analyzed using different TaqMan Assays-on-Demand and the ABPrism 7000 (both from Applied Biosystems, Foster City, Calif.). Data were analyzed using the ̂̂CT-method, which is commonly used for relative quantification (Livak K. J. and Schmittgen T. D., Methods, 25:402-40 (2001)). For normalization of expression data human glyceraldhyde-3 phosphate dehydrogenase was included as a housekeeping gene. For verification of normalization, a second housekeeping gene, β-2 microglobulin, was used as a control (data not shown).

Example 2 Clinical Outcome of Treatment of Subjects with IVIG

Analysis of the clinical outcome of the study showed that a 5-day course of IVIG therapy resulted in a significant reduction of the EDSS score in all 10 patients (FIG. 1). The effectiveness of the IVIG therapy was supported by an improvement of most MRI variables (Table 2). Although similar effects were observed in the control group that received standard treatment with IVMP (Table 2), the changes in MRI variables in the control group did not reach statistical significance. Treatment with IVIG was safe and well-tolerated.

TABLE 2 MRI analysis of brain abnormalities before and after treatment with IVIG and IVMP Before IVIG After IVIG Lesion vol cm³ Lesion vol cm³ Parameter mean ± SE mean ± SE T1 1.76 ± 0.55 1.73 ± 0.59  T2 5.49 ± 1.09 5.08 ± 1.03*  Flair 15.76 ± 2.23  14.09 ± 1.94**  Gd-enhanced 0.32 ± 0.27 0.21 ± 0.24** Brain volume 1124.94 ± 40.61  1120.31 ± 40.72   Gd + lesion N 2.83 ± 0.71 2.00 ± 0.60** EDSS score 3.8 ± 0.3 2.6 ± 0.2** Before IVMP After IVMP Lesion vol cm³ Lesion vol cm³ Parameter mean ± SE mean ± SE T1 1.41 ± 0.60 1.64 ± 0.84 T2 11.15 ± 4.59  9.83 ± 4.17 Flair 24.37 ± 8.19  23.18 ± 8.05  Gd-enhanced 0.70 ± 0.39 0.63 ± 0.37 Brain volume 1056.32 ± 47.78  1045.07 ± 52.53  Gd + lesion N 3.0 ± 1.5 2.7 ± 1.4 EDSS score 4.2 ± 2.0 3.3 ± 2.4 *p < 0.05; **p < 0.01 EDSS = Kurtzke's Expanded Disability Status Scale Gd = Gadolinium-enhanced lesion volumes

Example 3 Treatment with IVIG does not Significantly Alter the Cellular Composition of Cells Obtained for Isolation of RNA

PBMCs obtained from peripheral blood were separated into T cells and non-T cells using a mixture of non-stimulating anti-CD4+ and anti-CD8+ magnetic Dynabeads at 4° C. This procedure was chosen to prevent stimulation of T cells during cell separation. To ensure that potential differences in gene expression profiles are not due to differences in the cellular composition of the different samples, we compared the expression of genes that encode CD3, CD4, CD8 and CD14 between samples obtained at different time points for each patient. Our results show that the cellular composition of the samples obtained from each patient on different days is similar (FIGS. 2A, 2B). No statistically significant differences were observed.

Example 4 Analysis of Gene Expression Data Obtained from Patients Treated with IVIG

Statistic analysis of gene expression data included all results obtained from microarray analysis done at three different time points (before treatment, 1 day and 21 days after beginning of treatment) and included all 10 patients treated with IVIG. The analysis revealed that 360 genes in peripheral T cells were significantly changed in expression during the course of IVIG treatment. The expression of 91 of these genes changed between day 0 and day 6, the expression of 147 genes changed between day 0 and day 21, and the expression of 122 genes changed between day 6 and day 21.

Statistical analysis of the control-patient group treated with IVMP showed differential expression of 583 genes, with the majority (218 genes) being changed between day 0 and day 6.

Tables 3a-3d present the 20 most significant changes in gene expression observed in patients treated with IVIG and IVMP.

TABLE 3a 10 genes that were most extensively up-regulated in peripheral T cells of patients during IVIG therapy Fold Change Time Point Gene Title Gene Symbol Ref Seq ID 4.37 21 vs 6 Transcriptional regulating factor 1 TRERF1 NM_018415 4.26 21 vs 0 chromosome 19 open reading frame 28 C19orf28 NM_174983 4 6 vs 0 cyclin-dependent kinase inhibitor 1C (p57, Kip2) CDKN1C NM_000076 3.86 21 vs 6 breast cancer 1, early onset BRCA1 NM_007294 3.83 6 vs 0 Clone 23555 mRNA sequence — — 3.54 21 vs 6 — — — 3.52 21 vs 6 SH3-domain binding protein 4 SH3BP4 NM_014521 3.5 6 vs 0 collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant) COL3A1 NM_000090 3.41 21 vs 0 UDP-Gal:betaGlcNAc beta 1,3-galactosyltransferase, polypeptide 2 B3GALT2 NM_003783 3.36 21 vs 6 glycosylphosphatidylinositol specific phospholipase D1 GPLD1 NM_001503

TABLE 3b 10 genes that were most extensively down-regulated in peripheral T cells of patients during IVIG therapy Fold Change Time Point Gene Title Gene Symbol Ref Seq ID −4.82 6 vs 0 myotubularin related protein 7 MTMR7 NM_004686 −3.96 6 vs 0 transmembrane protein with EGF-like and two follistatin-like domains 1 TMEFF1 NM_003692 −3.9 21 vs 0 NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 5, 13 kDa NDUFA5 NM_005000 −3.89 21 vs 6 collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant) COL3A1 NM_000090 −3.59 21 vs 6 FAT tumor suppressor homolog 2 (Drosophila) FAT2 NM_001447 −3.57 21 vs 6 DNA damage repair and recombination protein RAD52 pseudogene — — −3.34 21 vs 0 chemokine (C-X-C motif) ligand 5 CXCL5 NM_002994 −3.34 21 vs 0 mesenchymal stem cell protein DSC43 LOC51333 NM_016643 −3.26 21 vs 6 natriuretic peptide receptor C/guanylate cyclase C (atrionatriuretic peptide receptor C) NPR3 NM_000908 −3.22 21 vs 6 early growth response 2 (Krox-20 homolog, Drosophila) EGR2 NM_000399 Table 3a/b: Timepoints: 6 vs) represents genes with a different expression between day 0 and day 6; 21 vs 0 represents genes with a differential expression between day 21 and day 0; and 21 vs 6 refers to genes with a change in expression between day 6 and day 21.

TABLE 3c 10 genes that were most extensively up-regulated in peripheral T cells of patients during IVMP therapy Fold Change Time Point Gene Title Gene Symbol Ref Seq ID 15.94 21 vs 6 leukocyte immunoglobulin-like receptor, subfamily A (without TM domain), member 4 ILT7 NM_012276 9.26 21 vs 6 prostaglandin D2 synthase 21 kDa (brain) PTGDS NM_000954 8.91 21 vs 6 Periostin, osteoblast specific factor POSTN NM_006475 8.64 21 vs 6 wingless-type MMTV integration site family, member 5A WNT5A NM_003392 8.31 21 vs 6 prostaglandin D2 synthase 21 kDa (brain) /// prostaglandin D2 synthase 21 kDa (brain) PTGDS NM_000954 7.94 21 vs 6 cyclin-dependent kinase inhibitor 1C (p57, Kip2) CDKN1C NM_000076 7.41 21 vs 6 cyclin-dependent kinase inhibitor 1C (p57, Kip2) CDKN1C NM_000076 7.33 6 vs 0 defensin, alpha 1, myeloid-related sequence /// defensin, alpha 3, neutrophil-specific DEFA1 /// NM_005217 6.48 6 vs 0 POU domain, class 1, transcription factor 1 (Pit1, growth hormone factor 1) POU1F1 NM_000306 6 6 vs 0 cadherin 13, H-cadherin (heart) CDH13 NM_001257

TABLE 3d 10 genes that were most extensively down-regulated in peripheral blood cells of patients during IVMP therapy Fold Change Time Point Gene Title Gene Symbol Ref Seq ID −11.52 6 vs 0 leukocyte immunoglobulin-like receptor, subfamily A (without TM domain), member 4 ILT7 NM_012276 −9.73 6 vs 0 tripartite motif-containing 58 TRIM58 NM_015431 −9.11 21 vs 6 Zwilch FLJ10036 NM_017975 −8.24 21 vs 0 Integrin, alpha 1 PELO NM_015946 −7.86 21 vs 0 zinc finger protein 6 (CMPX1) ZNF6 NM_021998 −7.36 21 vs 6 intersectin 1 (SH3 domain protein) ITSN1 NM_003024 −7.3 21 vs 6 phorbol-12-myristate-13-acetate-induced protein 1 PMA1P1 NM_021127 −7.28 21 vs 0 transmembrane protein 47 TMEM47 NM_031442 −6.84 6 vs 0 — — — −6.82 6 vs 0 prostaglandin D2 synthase 21 kDa (brain) PTGDS NM_000954 Table 3c/d: Timepoints: 6 vs 0 represents genes with a differential expression between day 0 and day 6; 21 vs 0 represents genes with a differential expression between day 21 and day 0; and 21 vs 6 refers to genes with a change in expression between day 6 and day 21.

Genes mostly affected in expression by IVIG treatment include genes that encode proteins that regulate cell cycle (transcriptional regulating factor 1, TRERF1; cyclin-dependent kinase inhibitor 1C, CDKN1C; breast cancer 1, BRCA 1; SH3-domain binding protein 4, SH3BP4); but also proteins that regulate inflammation [chemokine (C-X-C motif) ligand 5, CXCL5], cell adhesion (FAT tumor suppressor homolog 2, FAT2) or cell differentiation (early growth response, EGR2). Other genes included in the list encode proteins that are involved in electron transport, phosphorylation, glycosylation, skeletal development or proteins that have not yet been defined in function.

Other genes of interest that were differentially regulated upon IVIG treatment encoded proteins involved in immune regulation such as interleukin 11 (IL11), chemokine (C motif) ligand 2 (XCL2), prostaglandin E receptor 4 (PTGER4), caspase 2 (CASP2), killer cell immunoglobin-like receptor, two domains, short cytoplasmic tail 1 (KIR2DS1), mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2), chemokine (C-X-C motif) ligand 5 (CXCL5), chemokine (C-X-C motif) ligand 3 (CXCL3), C-type lectin domain family 4, member E (CLEC4E), chemokine (C-C motif) ligand 13 (CCL13) and alpha-fetoprotein (AFP) (see Table 4).

TABLE 4 Genes differentially expressed under IVIG treatment that encode proteins involved in immune regulation (note that accession number for CLEC4E should be NM_014358, not NM_013458 in Table 4). Fold Change Time Point Gene Title Gene Symbol Ref Seq ID 2.00 6 vs 0 interleukin 11 IL11 NM_000641 2.38 21 vs 0 chemokine (C motif) ligand 2 XCL2 NM_003175 2.28 21 vs 0 prostaglandin E receptor 4 (subtype EP4) PTGER4 NM_000958 2.02 21 vs 0 caspase 2, apoptosis-related cysteine protease (neural precursor cell expressed) CASP2 NM_032982 2.37 21 vs 6 killer cell immunoglobulin-like receptor, two domains, short cytoplasmic tail, 1 KIR2DS1 NM_014512 2.35 21 vs 0 mitogen-activated protein kinase kinase kinase kinase 2 MAP4K2 NM_004579 −3.34 21 vs 0 chemokine (C-X-C motif) ligand 5 CXCL5 NM_002994 −2.46 21 vs 0 chemokine (C-X-C motif) ligand 3 CXCL3 NM_002090 −2.26 21 vs 0 C-type lectin domain family 4, member E CLEC4E NM_013458 −3.06 21 vs 6 chemokine (C-C motif) ligand 13 CCL13 NM_005408 −2.53 21 vs 6 alpha-fetoprotein AFP NM_001134 Table 4: Timepoints: 6 vs 0 represents genes with a differential expression between day 0 and day 6; 21 vs 0 represents genes with a differential expression between day 21 and day 0; and 21 vs 6 refers to genes with a change in expression between day 6 and day 21.

Example 5 Comparison of Gene Expression Data Obtained from Patients Treated with IVIG and Patients Treated with IVMP

When gene expression data obtained from patients treated with IVIG were compared with gene expression data obtained from patients treated with IVMP, 17 genes were identified that significantly changed in expression in both groups of patients (Table 5). Most of the proteins that are encoded by these 17 genes regulate cell cycle (HABP4, STAT1, CDKN1, SH3BP4 and ORC1L). These results indicate that cell cycle regulation might be a mechanism of therapeutic effectiveness that both drugs have in common. The other genes that were found to be differentially regulated were only found in one of the two treatment groups and, therefore, reflect mechanisms of action that are specific for only one of the two drugs.

TABLE 5 Intersection of genes differentially expressed under both IVIG treatment and IVMP treatment Gene Title Gene Symbol GO Biological Process Description Ref Seq ID cadherin 5, type 2, VE-cadherin CDH5 cell adhesion /// homophilic cell adhesion NM_001795 (vascular epithelium) hyaluronan binding protein 4 HABP4 — NM_014282 signal transducer and activator STAT1 regulation of cell cycle /// transcription /// regulation of transcription, DNA- NM_007315 of transcription 1, 91 kDa dependent /// transcription from RNA polymerase II promoter /// caspase activation /// intracellular signaling cascade /// I-kappaB kinase/NF-kappaB cascade /// tyrosine phosp cyclin-dependent kinase CDKN1C regulation of cyclin dependent protein kinase activity /// G1 phase of NM_000076 inhibitor 1C (p57, Kip2) mitotic cell cycle /// cell cycle /// cell cycle arrest /// negative regulation of cell proliferation /// negative regulation of cell cycle actinin, alpha 2 ACTN2 — NM_001103 histone 1, H2bh HIST1H2BH nucleosome assembly /// nucleosome assembly /// chromosome NM_003524 organization and biogenesis (sensu Eukaryota) SH3-domain binding protein 4 SH3BP4 endocytosis /// cell cycle NM_014521 origin recognition complex, ORC1L DNA replication /// DNA replication initiation NM_004153 subunit 1-like (yeast) KIAA0644 gene product KIAA0644 — NM_014817 Heparan sulfate (glucosamine) HS3ST1 — NM_005114 3-O-sulfotransferase 1 ropporin, rhophilin associated ROPN1B cytokinesis /// signal transduction /// Rho protein signal transduction /// NM_001012337 protein 1B spermatogenesis /// acrosome reaction /// fusion of sperm to egg plasma membrane /// cell-cell adhesion /// sperm motility outer dense fiber of sperm ODF2 — NM_002540 tails 2 — — — unknown protein — — 1-acylglycerol-3-phosphate AGPAT7 metabolism NM_153613 O-acetyltransferase 7 zinc finger protein 804A ZNF804A — NM_194250 TRAF-type zinc finger domain TRAFD1 — NM_006700 containing 1

Example 6 Confirmation of Gene Expression Data Obtained with Microarray Analysis by Real-Time PCR

Data obtained with microarray analysis were confirmed by quantitative real-time PCR. For this purpose, 4 genes were selected that encoded proteins known to regulate immune regulation (see Table 4): PTGER4, CXCL5, IL11 and CASP2. Results of real-time PCR are shown in FIG. 3A-D. Results obtained with real-time PCR confirm the data obtained with microarray analysis (FIG. 3A-D, and Tables 3 and 4).

Discussion

The present study was designed to identify genes that are differentially expressed in peripheral T cells of patients with RRMS in acute exacerbation after treatment with IVIG. Peripheral T cells (CD4+ and CD8+ T cells) have been shown to be involved in the disease pathogenesis, in particular in the process of demyelination and axonal damage (Stinissen P. et al., Mult Scler., 4:203-11 (1998)). This is supported by a recent study in which a number of genes in peripheral blood cells of MS patients were shown to be differentially expressed compared with those in healthy twins (Särkijärvi S. et al., BMC Medical Genetics, 7:11 (2006)).

Statistical data analysis revealed 360 genes that were at least 2-fold up- or down-regulated in all patients following IVIG treatment. The effect of IVIG treatment was most prominent at 21 days after the beginning of IVIG treatment. Genes mostly affected in expression by IVIG treatment included genes that encode proteins that regulate cell cycle, signal transduction, transcription, inflammation, cell-cell interactions and apoptosis. These processes are likely to be involved in the pathogenesis of MS. When we compared the effects on gene expression caused by IVIG treatment with the effects caused by IVMP treatment, we found 583 genes to be differentially regulated upon IVMP treatment. The majority of these genes was altered in expression at day 6 compared to day 0 after the beginning of therapy. These results indicate that IVMP might be a faster acting drug than IVIG.

We identified 17 genes that were significantly changed in expression in both groups of patients. Most of the proteins that are encoded by these 17 genes regulate cell cycle. These results strongly suggest that the regulation of cell proliferation, in particular the regulation of T cell proliferation, is a mechanism of action that both drugs have in common. These results agree with published data that indicate that IVIG suppresses the proliferation of activated T cells when given to patients with MS (Andersson U. et al., Immunol Rev, 139:21-42 (1994); Bayry J. et al., Intravenous immunoglobulin in autoimmune disorders: An insight into the immunregulatory mechanisms).

An important mechanism of action of IVIG in MS seems to be the modulation of chemokine expression. This conclusion is based on our findings that a number of genes that encode chemokines (CXCL3, CXCL5, CCL13 and XCL2) are differentially expressed upon IVIG treatment. These changes in gene expression were not found in patients treated with IVMP. Therefore, we believe that the modulation of chemokine expression in peripheral T cells might be a specific mechanism of action of IVIG in MS. Several studies have shown that chemokines and chemokine receptors are involved in the pathogenesis of MS (Trebst C. and Ransohoff R. M., Arch Neurol, 58:1975-80 (2001)). Chemokines have been shown to mediate trafficking of immune cells across the blood-brain barrier and to direct migration of immune cells towards sites of active lesions (Szczucinski A. and Losy J., Acta Neurol Scand, 115:137-146 (2007)). Moreover, chemokines were detected in active lesions and were found to be elevated in the cerebrospinal fluid of patients with MS during relapse (Sindern E. et al., J Neuroimmunol, 131:186-90 (2002)). Two of the chemokines (CXCL3 and CXCL5) that were significantly down-regulated in our study are known to specifically interact with the chemokine receptor CXCR2 (Omari K. et al., Brain, 128:1003-1015 (2005)). Previous studies have shown that CXCR2 is not only expressed on peripheral blood cells such as granulocytes, monocytes or lymphocytes (Murdoch C. et al., Brain, 128:1003-1015 (2005(?)); Murphy P. M. et al., Pharmacol Rev., 52:145-76 (2000)) but also on oligodendrocytes in the brain. Oligodendrocytes are most essential for the myelination of axons in the white matter of the Central Nervous System and for remyelination after demyelination of axons during inflammation in MS (Blakemore W. F., J Neurol Sci., (2007)). Recently it was shown that CXCR2 expressed on oligodendrocytes is essential for the development and maintenance of the oligodendrocyte lineage, myelination and white matter in the vertebrate CNS (Tsai H. H. et al., Cell, 110:373-83 (2002); Padovani-Claudio D. et al., Glia, 54:471-483 (2006)). The regulation of oligodendrocyte development and migration depends on the localized expression of the chemokine CXCL1 and its interaction with CXCR2 expressed on oligodendrocyte precursor cells and oligodendrocytes (Padovani-Claudio D. et al., Glia, 54:471-483 (2006)). Any event that disrupts the interaction between CXCL1 and CXCR2 expressed on oligodendrocytes or the signalling induced by this interaction could therefore cause a disruption of the remyelination processes in MS patients. Based on these findings we propose the following hypothesis for a new mechanism of action of IVIG in RRMS patients during relapse. Peripheral T cells and monocytes enter the CNS in response to chemokines produced by the inflammation in the brain. The disrupted blood-brain barrier (Man S. et al., Brain Pathol., 17:243-50 (2007)) facilitates this process. Both T cells and monocytes produce chemokines in the brain that interfere with the tightly regulated activity of oligodendrocyte precursor cells and oligodendrocytes. This interference could be caused by either a desensitization of the CXCR2 receptor expressed on oligodendrocytes or by interference with the interaction between locally expressed CXCL1 and CXCR2 on oligodendrocytes. IVIG down-regulates the expression of chemokines in peripheral T cells, monocytes or both. Consequently, the interference of chemokines produced by these cells with the function of oligodendrocytes would be prevented and the natural process of remyelination induced by oligodendrocytes would be re-established. It remains to be shown whether IVIG might not only modulate the expression of chemokines in peripheral T cells but also the expression of chemokines in cells of the CNS, e.g., in astrocytes.

The aim of our study was to identify genes that are likely to be associated with T cell responses in MS. The strategy that we used for positive cell selection does not exclude the possibility that some of the identified genes are associated with peripheral monocytes rather than T cells. This has to be taken into consideration when interpreting the above data. The genes that we found to be differentially expressed under IVIG treatment will be confirmed in a second clinical trial with a larger study group. Differentially expressed genes can be used as diagnostic markers for the therapeutic efficacy of IVIG treatment. Furthermore, some of the proteins encoded by the genes of interest will provide suitable targets for future drug development.

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

INFORMAL SEQUENCE LISTING SEQ ID NO: 1: Homo sapiens transcriptional regulating factor 1 (TRERF1) (NM_018415) ctctgctcgc cccccatctc accccccaag cggatactgg tcttctcgtc ggattgccca tgcacttgtt gcagaaacag ccaaggccct ggctgtggag aatgctgaag gaagaagacg cagaagcagg acgaccctga aagattcagc ctcttcatcc tcaaacaggt cgcttctcgg gagttcttgg tgttggaata ttttacagca aagcagtcga ccaggcctcc tcttcccacc tgtccagcag catgaaagca gcatgattgg ccgaccgcag gagaagcccc cagaaccagg cccccaactc agccatctgc ggaggtcaag gtgtgagcga cgtctcctca ccacagtgct gtgtggtcta tacctcagcc agggagagga tgtgaaaccc cccgccctgc acatgagtgg tacaggccaa caggaacacc tggctccagc cacgttcaca gacatgtcag ccgtggagta gtgctgacac ttttctctca gcttctcagg gtttcagtcc ttttgggttt ggtttattta ccttttttat ggttttgtgg ctggacgttc acaaccaagg cagacagcat gggtgaccag caactgtaca agaccaacca tgtggcccat ggtagtgaga accttttcta ccaacagcca ccacttggcg tccacagcgg gctgagccca ctgatggcta ccaatacacc tactcccagg ccagcgagat ccggacccag aagcttacca gcggtgtctt acacaagctg gactctttca cccaggtgtt tgccaaccaa aacctgcgaa ttcaggtcaa caatatggcc caggtgctgc acactcagtc agcagtgatg gatggagccc ctgacagtgc tctccgccag ctgctgtctc agaagcccat ggagccccca gcaccggcta tcccttcccg ctaccagcag gtgccccagc agcctcaccc tggtttcact ggtgggctgt ccaaaccagc tcttcaggtc gggcagcacc ctacccaagg gcacctgtat tatgactacc agcagcctct ggctcaggtg ccagtgcagg gaggacagcc actgcaggcc ccacagatgc tgtcacagca catgcaacag atgcagcagc accagtatta cccaccgcag caacagcagc aagccgggca acagcgtatc tccatgcaag aaatacagac gcagccgcaa caaattcgcc catcacagcc acagccgccg ccacagcagc agcagccgca gcagctacag ctgcagcagc ggcagggttc aatgcagata cctcagtatt atcagcccca acccatgatg cagcacttgc aagagcagca gcagcaacag atgcacctgc agcctccttc ttatcacagg gaccctcacc agtatacccc agagcaggca cacactgtcc agctgattcc cctgggctcc atgtcccagt actactacca ggagccccag cagccctaca gccaccccct ttaccagcag agccacctgt cccagcacca gcagcgtgag gacagtcagc tgaagaccta ctctagtgac agacaggccc aggccatgct gagctcccat ggggacctgg ggcctcctga cacaggaatg ggagacccag cgagctcaga tctgacccgg gtcagcagca ccctccccca tcgccccctc ctatccccca gtgggatcca cctcaacaac atggggcctc agcatcagca gctgtctccc agtgccatgt ggccccagat gcacctacct gatgggagag cccagccagg gtcccctgag tcaagtggcc aacccaaagg agcgtttggg gagcagtttg atgccaagaa caagctgaca tgctccatct gcctgaagga gttcaagaac ctgcctgccc tgaatggcca catgcggtcc cacgggggaa tgagggcctc ccccaacctc aaacaggaaa tccccaggaa gcatcagccg agtgtgccca aagccgagga gcccctcaag accgtgcagg agaagaaaaa gttccggcac cggtcggaac ctctcttcat cccgccgccg ccctcctaca acccgaaccc cgctgcctcc tactcgggcg ccaccctgta ccagagccag ctgcgctccc cgcgcgtcct cggggaccac ctgctcctgg accccaccca cgagctgccc ccttacacgc ccccacccat gctgagcccg gtgcgccagg gctcggggct cttcagcaat gtcctcatct ccggccacgg ccctggcgcc cacccgcagc tgcccctgac gcccctgacg cccacaccac gggtgctgct gtgtcgctcc aacagcatcg atggcagcaa cgtgacggtc accccagggc ctggagagca gactgtagat gttgaaccac gcatcaacat tggcttgaga ttccaagcag aaatccctga actccaagat atctctgccc tggcccagga cacacacaag gccacactgg tatggaagcc ctggccagaa ctagaaaacc atgacctcca gcaaagagtg gagaatcttc tgaatttgtg ctgttccagt gcattgccag gtggagggac caattctgaa tttgctttgc actctctgtt tgaggccaaa ggtgatgtga tggttgctct ggaaatgctg ctactgcgga agcctgtcag gttaaaatgt catcctttag caaattacca ctatgccggt tcggacaagt ggacctccct agaaagaaaa ctgtttaaca aagcactagc cacttacagc aaagacttta tttttgtaca gaagatggtg aagtccaaga cggtggctca gtgcgtggag tactactaca cgtggaaaaa gatcatgcgg ctggggcgga aacaccggac acgcctggca gaaatcatcg acgattgtgt gacaagtgaa gaagaagaag agttagagga ggaggaggag gaggacccgg aagaagatag gaaatccaca aaagaagaag agagtgaggt gccgaagtcc ccggagccac cacccgtccc cgtcctggct cccacggagg ggccgcccct gcaggccctg ggccagccct caggctcctt catctgtgaa atgcccaact gtggggctga ctgtagatgt catgtcactc cctttcttcc ccaggtgttc agctcccgac aggcactgaa tggccatgcc cgcatccacg ggggcaccaa ccaggtgacc aaggcccgag gtgccatccc ctctgggaag cagaagcctg gtggcaccca gagtgggtac tgttcggtaa agagctcacc ctctcacagc accaccagcg gcgagacaga ccccaccacc atcttcccct gcaaggagtg tggcaaagtc ttcttcaaga tcaaaagccg aaatgcacac atgaaaactc acaggcagca ggaggaacaa cagaggcaaa aggctcagaa ggcggctttt gcagctgaga tggcagccac gattgagagg actacggggc ccgtgggggc gccggggctg ctgcccctgg accagctgag tctgatcaaa cccatcaagg atgtggacat cctcgacgac gacgtcgtcc agcagttggg aggtgtcatg gaagaggctg aagttgtgga caccgatctt ctcttggatg atcaagattc agtcttgctt cagggtgacg cagaactata aagccctgtg tgtcacttag agacagtgaa aacccacggc ctccatcttc attaatcagg aaacctggac tgcctgcttg ttttgtaacc cttttaaact acctgtttta aaagtggtca ttttattcag gtttagaaaa aaaaatccta tttcttttcc ttttatttaa aaaaatttgt ttttgtgggg ggttgggggg aataaataat tggcacaact aaaaaaaaaa aa SEQ ID NO: 2 Homo sapiens transcriptional regulating factor 1 (TRERF1) (NP_060885.1) MAQVLHTQSAVMDGAPDSALRQLLSQKPMEPPAPAIPSRYQQVPQQPHPGFTGGLSKPALQVGQHPTQGHLYYDY QQPLAQVPVQGGQPLQAPQMLSQHMQQMQQHQYYPPQQQQQAGQQRISMQEIQTQPQQIRPSQPQPPPQQQQPQQ LQLQQRQGSMQIPQYYQPQPMMQHLQEQQQQQMHLQPPSYHRDPHQYTPEQAHTVQLIPLGSMSQYYYQEPQQPY SHPLYQQSHLSQHQQREDSQLKTYSSDRQAQAMLSSHGDLGPPDTGMGDPASSDLTRVSSTLPHRPLLSPSGIHL NNMGPQHQQLSPSAMWPQMHLPDGRAQPGSPESSGQPKGAFGEQFDAKNKLTCSICLKEFKNLPALNGHMRSHGG MRASPNLKQEIPRKHQPSVPKAEEPLKTVQEKKKFRHRSEPLFIPPPPSYNPNPAASYSGATLYQSQLRSPRVLG DHLLLDPTHELPPYTPPPMLSPVRQGSGLFSNVLISGHGPGAHPQLPLTPLTPTPRVLLCRSNSIDGSNVTVTPG PGEQTVDVEPRINIGLRFQAEIPELQDISALAQDTHKATLVWKPWPELENHDLQQRVENLLNLCCSSALPGGGTN SEFALHSLFEAKGDVMVALEMLLLRKPVRLKCHPLANYHYAGSDKWTSLERKLFNKALATYSKDFIFVQKMVKSK TVAQCVEYYYTWKKIMRGRKHRTRLAEIIDDCVTSEEEEELEEEEEEDPEEDRKSTKEEESEVPKSPEPPPVPVL APTEGPPLQALGQPSGSFICEMPNCGADCRCHVTPFLPQVFSSRQALNGHARIHGGTNQVTKARGAIPSGKQKPG GTQSGYCSVKSSPSHSTTSGEDPTTIFPCKECGKVFFKIKSRNAHMKTHRQQEEQQRQKAQKAAFAAEMAATIER TTGPVGAPGLLPLDQLSLIKPIKDVDILDDDVVQQLGGVMEEAEVVDTDLLLDDQDSVLLQGDAEL SEQ ID NO: 3 Homo sapiens chromosome 19 open reading frame 28 (C19orf28) (NM_174983) tggggcggac gcggcggacg tgggtgaggg cgcggccgta agagagcggg acgcggggtg cccggcgcgt ggtgggggtc cccggcgcct gcccccacgg cacccaagaa ggcctggcca gggtaccctc cgcggagccc gggggtgggg ggcgcgggcc cggcgccgcg atgggcccgg gacccccagc ggccggagcg gcgccgtccc cgcggccgct gtccctggtg gcgcggctga gctacgccgt gggccacttc ctcaacgacc tgtgcgcgtc catgtggttc acctacctgc tgctctacct gcactcggtg cgcgcctaca gctcccgcgg cgcggggctg ctgctgctgc tgggccaggt ggccgacggg ctgtgcacac cgctcgtggg ctacgaggcc gaccgcgccg ccagctgctg cgcccgctac ggcccgcgca aggcctggca cctggtcggc accgtctgcg tcctgctgtc cttccccttc atcttcagcc cctgcctggg ctgtggggcg gccacgcccg agtgggctgc cctcctctac tacggcccgt tcatcgtgat cttccagttt ggctgggcct ccacacagat ctcccacctc agcctcatcc cggagctcgt caccaacgac catgagaagg tggagctcac ggcactcagg tatgcgttca ccgtggtggc caacatcacc gtctacggcg ccgcctggct cctgctgcac ctgcagggct cgtcgcgggt ggagcccacc caagacatca gcatcagcga ccagctgggg ggccaggacg tgcccgtgtt ccggaacctg tccctgctgg tggtgggtgt cggcgccgtg ttctcactgc tattccacct gggcacccgg gagaggcgcc ggccgcatgc ggaggagcca ggcgagcaca cccccctgtt ggcccctgcc acggcccagc ccctgctgct ctggaagcac tggctccggg agccggcttt ctaccaggtg ggcatactgt acatgaccac caggctcatc gtgaacctgt cccagaccta catggccatg tacctcacct actcgctcca cctgcccaag aagttcatcg cgaccattcc cctggtgatg tacctcagcg gcttcttgtc ctccttcctc atgaagccca tcaacaagtg cattgggagg aacatgacct acttctcagg cctcctggtg atcctggcct ttgccgcctg ggtggcgctg gcggagggac tgggtgtggc cgtgtacgca gcggctgtgc tgctgggtgc tggctgtgcc accatcctcg tcacctcgct ggccatgacg gccgacctca tcggtcccca cacgaacagc ggagcgttcg tgtacggctc catgagcttc ttggataagg tggccaatgg gctggcagtc atggccatcc agagcctgca cccttgcccc tcagagctct gctgcagggc ctgcgtgagc ttttaccact gggcgatggt ggctgtgacg ggcggcgtgg gcgtggccgc tgccctgtgt ctctgtagcc tcctgctgtg gccgacccgc ctgcgacgct gggaccgtga tgcccggccc tgactcctga cagcctcctg cacctgtgca agggaactgt ggggacgcac gaggatgccc cccagggcct tggggaaaag cccccactgc ccctcactct tctctggacc cccaccctcc atcctcaccc agctcccggg ggtggggtcg ggtgagggca gcagggatgc ccgccaggga cttgcaagga ccccctgggt tttgagggtg tcccattctc aactctaatc catcccagcc ctctggagga tttggggtgc ccctctcggc agggaacagg aagtaggaat cccagaaggg tctgggggaa ccctaaccct gagctcagtc cagttcaccc ctcacctcca gcctgggggt ctccagacac tgccagggcc ccctcaggac ggctggagcc tggaggagac agccacgggg tggtgggctg ggcctggacc ccaccgtggt gggcagcagg gctgcccggc aggcttggtg gactctgctg gcagcaaata aagagatgac ggcaaaaaaa aaaaaaaa SEQ ID NO: 4 Homo sapiens chromosome 19 open reading frame 28 (C19orf28) (NP_778148.2) MGPGPPAAGAAPSPRPLSLVARLSYAVGHFLNDLCASMWFTYLLLYLHSVRAYSSRGAGLLLLLGQVADGLCTPL VGYEADRAASCCARYGPRKAWHLVGTVCVLLSFPFIFSPCLGCGAATPEWAALLYYGPFIVIFQFGWASTQISHL SLIPELVTNDHEKVELTALRYAFTVVANITVYGAAWLLLHLQGSSRVEPTQDISISDQLGGQDVPVFRNLSLLVV GVGAVFSLLFHLGTRERRRPHAEEPGEHTPLLAPATAQPLLLWKHWLREPAFYQVGILYMTTRLIVNLSQTYMAM YLTYSLHLPKKFIATIPLVMYLSGFLSSFLMKPINKCIGRNMTYFSGLLVILAFAAWVALAEGLGVAVYAAAVLL GAGCATILVTSLAMTADLIGPHTNSGAFVYGSMSFLDKVANGLAVMAIQSLHPCPSELCCRACVSFYHWAMVAVT GGVGVAAALCLCSLLLWPTRLRRWDRDARP SEQ ID NO: 5 Homo sapiens cyclin-dependent kinase inhibitor 1C (p57, Kip2) (NM_000076) gaattccggg cacccctcga gcgagcgagc tagccagcag gcatcgaggg ggcgcggctg ccgtccggac gagacaggcg aacccgacgc agaagagtcc accaccggac agtcaggtag ccgccgcgtc cctcgcacac gcagagtcgg gcggcgcggg gtctcccttg cgcccggcct ccgccctctc ctcctctcct ttccccttct tctcgctgtc ctctcctctc tcgctgcccg cgtttgcgca gccccgggcc atgtccgacg cgtccctccg cagcacatcc acgatggagc gtcttgtcgc ccgtgggacc ttcccagtac tagtgcgcac cagcgcctgc cgcagcctct tcgggccggt ggaccacgag gagctgagcc gcgagctgca ggcccgcctg gccgagctga acgccgagga ccagaaccgc tgggattacg acttccagca ggacatgccg ctgcggggcc ctggacgcct gcagtggacc gaagtggaca gcgactcggt gcccgcgttc taccgcgaga cggtgcaggt ggggcgctgc cgcctgctgc tggcgccgcg gcccgtcgcg gtcgcggtgg ctgtcagccc gcccctcgag ccggccgctg agtccctcga cggcctcgag gaggcgccgg agcagctgcc tagtgtcccg gtcccggccc cggcgtccac cccgccccca gtcccggtcc tggctccagc cccggccccg gctccggctc cggtcgcggc tccggtcgcg gctccggtcg cggtcgcggt cctggccccg gccccggccc cggccccggc tccggctccg gccccggctc cagtcgcggc cccggcccca gccccggccc cggccccggc cccggccccc gccccggccc cggccccgga cgcggcgcct caagagagcg ccgagcaggg cgcgaaccag gggcagcgcg gccaggagcc tctcgctgac cagctgcact cggggatttc gggacgtccc gcggccggca ccgcggccgc cagcgccaac ggcgcggcga tcaagaagct gtccgggcct ctgatctccg atttcttcgc caagcgcaag agatcagcgc ctgagaagtc gtcgggcgat gtccccgcgc cgtgtccctc tccaagcgcc gcccctggcg tgggctcggt ggagcagacc ccgcgcaaga ggctgcggtg agccaattta gagcccaaag agccccgagg gaacctgccg gggcagcgga cgttggaagg gcgctgggcc tcggctggga ccgttcatgt agcagcaacc ggcggcggct gccgcagagc agcgttcggt tttgttttta aattttgaaa actgtgcaat gtattaataa cgtcttttta tatctaaatg tattctgcac gagaaggtac actggtccca aagtgtaaag ctttaagagt catttatata aaatgtttaa tctctgctga aactcagtac aaaaaaaccg ggattccggc c SEQ ID NO: 6 Homo sapiens cyclin-dependent kinase inhibitor 1C (p57, Kip2) (NP_000067.1) MSDASLRSTSTMERLVARGTFPVLVRTSACRSLFGPVDHEELSRELQARLAELNAEDQNRWDYDFQQDMPLRGPG RLQWTEVDSDSVPAFYRETVQVGRCRLLLAPRPVAVAVAVSPPLEPAAESLDGLEEAPEQLPSVPVPAPASTPPP VPVLAPAPAPAPAPVAAPVAAPVAVAVLAPAPAPAPAPAPAPAPVAAPAPAPAPAPAPAPAPAPAPDAAPQESAE QGANQGQRGQEPLADQLHSGISGRPAAGTAAASANGAAIKKLSGPLISDFFAKRKRSAPEKSSGDVPAPCPSPSA APGVGSVEQTPRKRLR SEQ ID NO: 7 Homo sapiens breast cancer 1, early onset (BRCA1) (NM_007294) cttagcggta gccccttggt ttccgtggca acggaaaagc gcgggaatta cagataaatt aaaactgcga ctgcgcggcg tgagctcgct gagacttcct ggacggggga caggctgtgg ggtttctcag ataactgggc ccctgcgctc aggaggcctt caccctctgc tctgggtaaa gttcattgga acagaaagaa atggatttat tgctcttcg cgttgaagaa gtacaaaatg tcattaatgc tatgcagaaa atcttagagt gtcccatctg tctggagttg atcaaggaac ctgtctccac aaagtgtgac cacatatttt gcaaattttg catgctgaaa cttctcaacc agaagaaagg gccttcacag tgtcctttat gtaagaatga tataaccaaa aggagcctac aagaaagtac gagatttagt caacttgttg aagagctatt gaaaatcatt tgtgcttttc agcttgacac aggtttggag tatgcaaaca gctataattt tgcaaaaaag gaaaataact ctcctgaaca tctaaaagat gaagtttcta tcatccaaag tatgggctac agaaaccgtg ccaaaagact tctacagagt gaacccgaaa atccttcctt gcaggaaacc agtctcagtg tccaactctc taaccttgga actgtgagaa ctctgaggac aaagcagcgg atacaacctc aaaagacgtc tgtctacatt gaattgggat ctgattcttc tgaagatacc gttaataagg caacttattg cagtgtggga gatcaagaat tgttacaaat cacccctcaa ggaaccaggg atgaaatcag tttggattct gcaaaaaagg ctgcttgtga attttctgag acggatgtaa caaatactga acatcatcaa cccagtaata atgatttgaa caccactgag aagcgtgcag ctgagaggca tccagaaaag tatcagggta gttctgtttc aaacttgcat gtggagccat gtggcacaaa tactcatgcc agctcattac agcatgagaa cagcagttta ttactcacta aagacagaat gaatgtagaa aaggctgaat tctgtaataa aagcaaacag cctggcttag caaggagcca acataacaga tgggctggaa gtaaggaaac atgtaatgat aggcggactc ccagcacaga aaaaaaggta gatctgaatg ctgatcccct gtgtgagaga aaagaatgga ataagcagaa actgccatgc tcagagaatc ctagagatac tgaagatgtt ccttggataa cactaaatag cagcattcag aaagttaatg agtggttttc cagaagtgat gaactgttag gttctgatga ctcacatgat ggggagtctg aatcaaatgc caaagtagct gatgtattgg acgttctaaa tgaggtagat gaatattctg gttcttcaga gaaaatagac ttactggcca gtgatcctca tgaggcttta atatgtaaaa gtgaaagagt tcactccaaa tcagtagaga gtaatattga agacaaaata tttgggaaaa cctatcggaa gaaggcaagc ctccccaact taagccatgt aactgaaaat ctaattatag gagcatttgt tactgagcca cagataatac aagagcgtcc cctcacaaat aaattaaagc gtaaaaggag acctacatca ggccttcatc ctgaggattt tatcaagaaa gcagatttgg cagttcaaaa gactcctgaa atgataaatc agggaactaa ccaaacggag cagaatggtc aagtgatgaa tattactaat agtggtcatg agaataaaac aaaaggtgat tctattcaga atgagaaaaa tcctaaccca atagaatcac tcgaaaaaga atctgctttc aaaacgaaag ctgaacctat aagcagcagt ataagcaata tggaactcga attaaatatc cacaattcaa aagcacctaa aaagaatagg ctgaggagga agtcttctac caggcatatt catgcgcttg aactagtagt cagtagaaat ctaagcccac ctaattgtac tgaattgcaa attgatagtt gttctagcag tgaagagata aagaaaaaaa agtacaacca aatgccagtc aggcacagca gaaacctaca actcatggaa ggtaaagaac ctgcaactgg agccaagaag agtaacaagc caaatgaaca gacaagtaaa agacatgaca gcgatacttt cccagagctg aagttaacaa atgcacctgg ttcttttact aagtgttcaa ataccagtga acttaaagaa tttgtcaatc ctagccttcc aagagaagaa aaagaagaga aactagaaac agttaaagtg tctaataatg ctgaagaccc caaagatctc atgttaagtg gagaaagggt tttgcaaact gaaagatctg tagagagtag cagtatttca ttggtacctg gtactgatta tggcactcag gaaagtatct cgttactgga agttagcact ctagggaagg caaaaacaga accaaataaa tgtgtgagtc agtgtgcagc atttgaaaac cccaagggac taattcatgg ttgttccaaa gataatagaa atgacacaga aggctttaag tatccattgg gacatgaagt taaccacagt cgggaaacaa gcatagaaat ggaagaaagt gaacttgatg ctcagtattt gcagaataca ttcaaggttt caaagcgcca gtcatttgct ccgttttcaa atccaggaaa tgcagaagag gaatgtgcaa cattctctgc ccactctggg tccttaaaga aacaaagtcc aaaagtcact tttgaatgtg aacaaaagga agaaaatcaa ggaaagaatg agtctaatat caagcctgta cagacagtta atatcactgc aggctttcct gtggttggtc agaaagataa gccagttgat aatgccaaat gtagtatcaa aggaggctct aggttttgtc tatcatctca gttcagaggc aacgaaactg gactcattac tccaaataaa catggacttt tacaaaaccc atatcgtata ccaccacttt ttcccatcaa gtcatttgtt aaaactaaat gtaagaaaaa tctgctagag gaaaactttg aggaacattc aatgtcacct gaaagagaaa tgggaaatga gaacattcca agtacagtga gcacaattag ccgtaataac attagagaaa atgtttttaa agaagccagc tcaagcaata ttaatgaagt aggttccagt actaatgaag tgggctccag tattaatgaa ataggttcca gtgatgaaaa cattcaagca gaactaggta gaaacagagg gccaaaattg aatgctatgc ttagattagg ggttttgcaa cctgaggtct ataaacaaag tcttcctgga agtaattgta agcatcctga aataaaaaag caagaatatg aagaagtagt tcagactgtt aatacagatt tctctccata tctgatttca gataacttag aacagcctat gggaagtagt catgcatctc aggtttgttc tgagacacct gatgacctgt tagatgatgg tgaaataaag gaagatacta gttttgctga aaatgacatt aaggaaagtt ctgctgtttt tagcaaaagc gtccagaaag gagagcttag caggagtcct agccctttca cccatacaca tttggctcag ggttaccgaa gaggggccaa gaaattagag tcctcagaag agaacttatc tagtgaggat gaagagcttc cctgcttcca acacttgtta tttggtaaag taaacaatat accttctcag tctactaggc atagcaccgt tgctaccgag tgtctgtcta agaacacaga ggagaattta ttatcattga agaatagctt aaatgactgc agtaaccagg taatattggc aaaggcatct caggaacatc accttagtga ggaaacaaaa tgttctgcta gcttgttttc ttcacagtgc agtgaattgg aagacttgac tgcaaataca aacacccagg atcctttctt gattggttct tccaaacaaa tgaggcatca gtctgaaagc cagggagttg gtctgagtga caaggaattg gtttcagatg atgaagaaag aggaacgggc ttggaagaaa ataatcaaga agagcaaagc atggattcaa acttaggtga agcagcatct gggtgtgaga gtgaaacaag cgtctctgaa gactgctcag ggctatcctc tcagagtgac attttaacca ctcagcagag ggataccatg caacataacc tgataaagct ccagcaggaa atggctgaac tagaagctgt gttagaacag catgggagcc agccttctaa cagctaccct tccatcataa gtgactcttc tgcccttgag gacctgcgaa atccagaaca aagcacatca gaaaaagcag tattaacttc acagaaaagt agtgaatacc ctataagcca gaatccagaa ggcctttctg ctgacaagtt tgaggtgtct gcagatagtt ctaccagtaa aaataaagaa ccaggagtgg aaaggtcatc cccttctaaa tgcccatcat tagatgatag gtggtacatg cacagttgct ctgggagtct tcagaataga aactacccat ctcaagagga gctcattaag gttgttgatg tggaggagca acagctggaa gagtctgggc cacacgattt gacggaaaca tcttacttgc caaggcaaga tctagaggga accccttacc tggaatctgg aatcagcctc ttctctgatg accctgaatc tgatccttct gaagacagag ccccagagtc agctcgtgtt ggcaacatac catcttcaac ctctgcattg aaagttcccc aattgaaagt tgcagaatct gcccagagtc cagctgctgc tcatactact gatactgctg ggtataatgc aatggaagaa agtgtgagca gggagaagcc agaattgaca gcttcaacag aaagggtcaa caaaagaatg tccatggtgg tgtctggcct gaccccagaa gaatttatgc tcgtgtacaa gtttgccaga aaacaccaca tcactttaac taatctaatt actgaagaga ctactcatgt tgttatgaaa acagatgctg agtttgtgtg tgaacggaca ctgaaatatt ttctaggaat tgcgggagga aaatgggtag ttagctattt ctgggtgacc cagtctatta aagaaagaaa aatgctgaat gagcatgatt ttgaagtcag aggagatgtg gtcaatggaa gaaaccacca aggtccaaag cgagcaagag aatcccagga cagaaagatc ttcagggggc tagaaatctg ttgctatggg cccttcacca acatgcccac agatcaactg gaatggatgg tacagctgtg tggtgcttct gtggtgaagg agctttcatc attcaccctt ggcacaggtg tccacccaat tgtggttgtg cagccagatg cctggacaga ggacaatggc ttccatgcaa ttgggcagat gtgtgaggca cctgtggtga cccgagagtg ggtgttggac agtgtagcac tctaccagtg ccaggagctg gacacctacc tgatacccca gatcccccac agccactact gactgcagcc agccacaggt acagagccac aggaccccaa gaatgagctt acaaagtggc ctttccaggc cctgggagct cctctcactc ttcagtcctt ctactgtcct ggctactaaa tattttatgt acatcagcct gaaaaggact tctggctatg caagggtccc ttaaagattt tctgcttgaa gtctcccttg gaaatctgcc atgagcacaa aattatggta atttttcacc tgagaagatt ttaaaaccat ttaaacgcca ccaattgagc aagatgctga ttcattattt atcagcccta ttctttctat tcaggctgtt gttggcttag ggctggaagc acagagtggc ttggcctcaa gagaatagct ggtttcccta agtttacttc tctaaaaccc tgtgttcaca aaggcagaga gtcagaccct tcaatggaag gagagtgctt gggatcgatt atgtgactta aagtcagaat agtccttggg cagttctcaa atgttggagt ggaacattgg ggaggaaatt ctgaggcagg tattagaaat gaaaaggaaa cttgaaacct gggcatggtg gctcacgcct gtaatcccag cactttggga ggccaaggtg ggcagatcac tggaggtcag gagttcgaaa ccagcctggc caacatggtg aaaccccatc tctactaaaa atacagaaat tagccggtca tggtggtgga cacctgtaat cccagctact caggtggcta aggcaggaga atcacttcag cccgggaggt ggaggttgca gtgagccaag atcataccac ggcactccag cctgggtgac agtgagactg tggctcaaaa aaaaaaaaaa aaaaaggaaa atgaaactag aagagatttc taaaagtctg agatatattt gctagatttc taaagaatgt gttctaaaac agcagaagat tttcaagaac cggtttccaa agacagtctt ctaattcctc attagtaata agtaaaatgt ttattgttgt agctctggta tataatccat tcctcttaaa atataagacc tctggcatga atatttcata tctataaaat gacagatccc accaggaagg aagctgttgc tttctttgag gtgatttttt tcctttgctc cctgttgctg aaaccataca gcttcataaa taattttgct tgctgaagga agaaaaagtg tttttcataa acccattatc caggactgtt tatagctgtt ggaaggacta ggtcttccct agccccccca gtgtgcaagg gcagtgaaga cttgattgta caaaatacgt tttgtaaatg ttgtgctgtt aacactgcaa ataaacttgg tagcaaacac ttcaaaaaaa aaaaaaaaaa a SEQ ID NO: 8 Homo sapiens breast cancer 1, early onset (BRCA1) (NP_009225.1) MDLSALRVEEVQNVINAMQKILECPICLELIKEPVSTKCDHIFCKFCMLKLLNQKKGPSQCPLCKNDITKRSLQE STRFSQLVEELLKIICAFQLDTGLEYANSYNFAKKENNSPEHLKDEVSIIQSMGYRNRAKRLLQSEPENPSLQET SLSVQLSNLGTVRTLRTKQRIQPQKTSVYIELGSDSSEDTVNKATYCSVGDQELLQITPQGTRDEISLDSAKKAA CEFSETDVTNTEHHQPSNNDLNTTEKRAAERHPEKYQGSSVSNLHVEPCGTNTHASSLQHENSSLLLTKDRMNVE KAEFCNKSKQPGLARSQHNRWAGSKETCNDRRTPSTEKKVDLNADPLCERKEWNKQKLPCSENPRDTEDVPWITL NSSIQKVNEWFSRSDELLGSDDSHDGESESNAKVADVLDVLNEVDEYSGSSEKIDLLASDPHEALICKSERVHSK SVESNIEDKIFGKTYRKKASLPNLSHVTENLIIGAFVTEPQIIQERPLTNKLKRKRRPTSGLHPEDFIKKADLAV QKTPEMINQGTNQTEQNGQVMNITNSGHENKTKGDSIQNEKNPNPIESLEKESAFKTKAEPISSSISNMELELNI HNSKAPKKNRLRRKSSTRHIHALELVVSRNLSPPNCTELQIDSCSSSEEIKKKKYNQMPVRHSRNLQLMEGKEPA TGAKKSNKPNEQTSKRHDSDTFPELKLTNAPGSFTKCSNTSELKEFVNPSLPREEKEEKLETVKVSNNAEDPKDL MLSGERVLQTERSVESSSISLVPGTDYGTQESISLLEVSTLGKAKTEPNKCVSQCAAFENPKGLIHGCSKDNRND TEGFKYPLGHEVNHSRETSIEMEESELDAQYLQNTFKVSKRQSFAPFSNPGNAEEECATFSAHSGSLKKQSPKVT FECEQKEENQGKNESNIKPVQTVNITAGFPVVGQKDKPVDNAKCSIKGGSRFCLSSQFRGNETGLITPNKHGLLQ NPYRIPPLFPIKSFVKTKCKKNLLEENFEEHSMSPEREMGNENIPSTVSTISRNNIRENVFKEASSSNINEVGSS TNEVGSSINEIGSSDENIQAELGRNRGPKLNAMLRLGVLQPEVYKQSLPGSNCKHPEIKKQEYEEVVQTVNTDFS PYLISDNLEQPMGSSHASQVCSETPDDLLDDGEIKEDTSFAENDIKESSAVFSKSVQKGELSRSPSPFTHTHLAQ GYRRGAKKLESSEENLSSEDEELPCFQHLLFGKVNNIPSQSTRHSTVATECLSKNTEENLLSLKNSLNDCSNQVI LAKASQEHHLSEETKCSASLFSSQCSELEDLTANTNTQDPFLIGSSKQMRHQSESQGVGLSDKELVSDDEERGTG LEENNQEEQSMDSNLGEAASGCESETSVSEDCSGLSSQSDILTTQQRDTMQHNLIKLQQEMAELEAVLEQHGSQP SNSYPSIISDSSALEDLRNPEQSTSEKAVLTSQKSSEYPISQNPEGLSADKFEVSADSSTSKNKEPGVERSSPSK CPSLDDRWYMHSCSGSLQNRNYPSQEELIKVVDVEEQQLEESGPHDLTETSYLPRQDLEGTPYLESGISLFSDDP ESDPSEDRAPESARVGNIPSSTSALKVPQLKVAESAQSPAAAHTTDTAGYNAMEESVSREKPELTASTERVNKRM SMVVSGLTPEEFMLVYKFARKHHITLTNLITEETTHVVMKTDAEFVCERTLKYFLGIAGGKWVVSYFWVTQSIKE RKMLNEHDFEVRGDVVNGRNHQGPKRARESQDRKIFRGLEICCYGPFTNMPTDQLEWMVQLCGASVVKELSSFTL GTGVHPIVVVQPDAWTEDNGFHAIGQMCEAPVVTREWVLDSVALYQCQELDTYLIPQIPHSHY SEQ ID NO: 9 Homo sapiens SH3-domain binding protein 4 (SH3BP4)(NM_014521) gggaccaccc tccgcccgcc gaggcggggg cccagcgcgc ccggcactct cggcggtccg ggcccctcgc cactaccgcc gccgccgccg ccgtgagtcc cgcggagccg cgcgcgcccc cggctgggcc gagccgctgg ccgacgagcg gagcctcagg agccggcggg gacgccatgc gagccagcgt ctcccttctc tcctggacag aaggccgtgt cctgggactt ctctgatggc gagaggctgc ggctgtacca ggaagaaaca tattgccgag tggatgccgc cgcgcagcgt gtttgcttga ggcagaagct tcagcatctg ctgggataac tggaggaaga aatatgaagc cttagcggct ttacccggga agcgagtttc gagatggcgg ctcagcggat ccgagcggcc aactccaatg gcctccctcg ctgcaagtca gaggggaccc tgattgacct gagcgaaggg ttttcagaga cgagctttaa tgacatcaaa gtgccttctc ccagtgcctt gctcgtagac aaccccacac ctttcggaaa tgcaaaggaa gtgattgcga tcaaggacta ttgccccacc aacttcacca cactgaagtt ctccaagggc gaccatctct acgtcttgga cacatctggc ggtgagtggt ggtacgcaca caacaccacc gaaatgggct acatcccctc ctcctatgtg cagcccttga actaccggaa ctcaacactg agtgacagcg gtatgattga taatcttcca gacagcccag acgaggtagc caaggagctg gagctgctcg ggggatggac agatgacaaa aaagtaccag gcagaatgta cagtaataac cctttctgga atggggtcca gaccaatcca tttctgaatg ggaacgtgcc cgtcatgccc agcctggatg agctgaatcc caaaagtact gtggatttgc tcctttttga cgcaggtaca tcctccttca ccgaatccag ctcagccacc acgaatagca ctggcaacat cttcgatgag cttccagtca caaacggact ccacgcagag ccgccggtca ggcgggacaa ccccttcttc agaagcaagc gctcctacag tctctcggaa ctctccgtcc tccaagccaa gtccgatgct cccacatcgt cgagtttctt caccggcttg aaatcacctg cccccgagca atttcagagc cgggaggatt ttcgaactgc ctggctaaac cacaggaagc tggcccggtc ttgccacgac ctggacttgc ttggccaaag ccctggttgg ggccagaccc aagccgtgga gacaaacatc gtgtgcaagc tggatagctc cgggggtgct gtccagcttc ctgacaccag catcagcatc cacgtgcccg agggccacgt cgcccctggg gagacccagc agatctccat gaaagccctg ctggaccccc cgctggagct caacagtgac aggtcctgca gcatcagccc tgtgctggag gtcaagctga gcaacctgga ggtgaaaacc tctatcatct tggagatgaa agtgtcagcc gagataaaaa atgacctttt tagcaaaagc acagtgggcc tccagtgcct gaggagcgac tcgaaggaag ggccatatgt ctccgtcccg ctcaactgca gctgtgggga cacggtccag gcacagctgc acaacctgga gccctgtatg tacgtggctg tcgtggccca tggcccaagc atcctctacc cttccaccgt gtgggacttc atcaataaaa aagtcacagt gggtctctac ggccctaaac acatccaccc atccttcaag acggtagtga ccatttttgg gcatgactgt gccccaaaga cgctcctggt cagcgaggtc acacgccagg cacccaaccc tgccccggtg gccctgcagc tgtgggggaa gcaccagttc gttttgtcca ggccccagga tctcaaggtc tgtatgtttt ccaatatgac gaattacgag gtcaaagcca gcgagcaggc caaagtggtg cgaggattcc agctgaagct gggcaaggtg agccgcctga tcttccccat cacctcccag aaccccaacg agctctctga cttcacgctg cgggttcagg tgaaggacga ccaggaggcc atcctcaccc agttttgtgt ccagactcct cagccacccc ctaaaagtgc catcaagcct tccgggcaaa ggaggtttct caagaagaac gaagtcggga aaatcatcct gtccccgttt gccaccacta caaagtaccc gactttccag gaccgcccgg tgtccagcct caagtttggt aagttgctca agactgtggt gcggcagaac aagaaccact acctgctgga gtacaagaag ggcgacggga tcgccctgct cagcgaggag cgggtcaggc tccggggcca gctgtggacc aaggagtggt acatcggcta ctaccagggc agggtgggcc tcgtgcacac caagaacgtg ctggtggtcg gcagggcccg gcccagcctg tgctcgggcc ccgagctgag cacctcggtg ctgctggagc agatcctgcg gccctgcaaa ttcctcacgt acatctatgc ctccgtgagg accctgctca tggagaacat cagcagctgg cgctccttcg ctgacgccct gggctacgtg aacctgccgc tcaccttttt ctgccgggca gagctggata gtgagcccga gcgggtggcg tccgtcctag aaaagctgaa ggaggactgt aacaacactg agaacaaaga acggaagtcc ttccagaagg agcttgtgat ggccctactg aagatggact gccagggcct ggtggtcaga ctcatccagg actttgtgct cctgaccacg gctgtagagg tggcccagcg ctggcgggag ctggctgaga agctggccaa ggtctccaag cagcagatgg acgcctacga gtctccccac cgggacagga acggggttgt ggacagcgag gccatgtgga agcctgcgta tgacttctta ctcacctgga gccatcagat cggggacagc taccgggatg tcatccagga gctgcacctg ggcctggaca agatgaaaaa ccccatcacc aagcgctgga agcacctcac tgggactctg atcttggtga actccctgga cgttctgaga gcagccgcct tcagccctgc ggaccaggac gacttcgtga tttgaatggg tcccctcccc tcctgctgct ctggagtgca agccctcttc tgccctgcgt gccctgctgt caccgcggag ctgaagaggg aggaaggggc ggctgctcag acagatttag ggcccgccag ctaggctaca cccatcatgc gccgccctcc tccatcgagg gagaggcctg aagggactgc ctactgcagc tcgttgccaa tcacatagct ttctatttgt taagtataaa tttaaattta aaatcacttt tttaacgaat ggggggaagg gatctatgag aaaggtggta tctaattttt ttatggacca taaaggttta aaagaaaata ggggcacagg ctgttgaggt ttttatgttg ttatagacct ttttaaatta tgttagagat gtatataggt atttaaaggt cactgggagc gtttctgatt cccggccaca ctttgcattt caacactcag cccggaaaga tgctcgttcg gttgttggac ctctttcact ccctgcgtgt aagaaggtga atcacgtggg aaaaagtggc ttttcagtaa acgggtacag ctcattcttt ctgagaaggc cccaggtcct gctccctcct cggatttgat tgtcttccgt gctttgcctc actcgtagta aatgaccatc catagaatat gtgaatcttt ggtgagcttc agtgggcaga gtgaagtccc gcattagcat ttaggtgccc tgagctgttt ctgccaatag attagaaagc agccatgagt tgacagtctt tagggcccct gccagtgtgc aattagtcat tgacaagaac aatgccattt gagagtgagg tggtccctgc tgctacgagg ccattgtact gttttttcct tgaggtcaaa gcagtgcttc ccatagagtt tgctgcctct tctgtggaca ggaagaaaac ttcatgaccg aatcagagcc ttggtggcca ctgactctcg tgcttattgc agatgctgtg gttggcctca caagcaacgc cttatgctga tgtgcagagg tgccagctgc catttgccaa actctgcatt tcatttcatc taaggcttaa cccctcttcc ttcctggtgt acctgtgtct cctcggaagg aagtcatagt ttagatgaaa ccattttttg tacaatgtaa agatcatctg agcaagatga gcattttgta aaaatgaaaa tgtgactcac ataaaatcag gaacttgaca cagtgttgca ttaataactt tagggtgcag acatgctgtg tgaatctcac aatgcgtcgt agatgtcgcg tgttggaagg gagcaggagg aaggactgat actggcaaat cagtagagtg aggtgatcct tagcaacgtg ccaggacact tcctgtgtgc ctgcagttgt cagggaccat ttgggatccc gaatctcatt ctctaaaact gctttcttga aacatgttac ttccttagta taatcaatgt atactccctt actggcctga aacgttgtat agctacttat tcagatactg aagaccaacg gactgaaaaa aagaacaaac attagctatt ttatgctgca agaaccagga cacacaattc gccaatcatc ccaccatata accttcgatt gtgcttctca actccacccc ataatttctc ccagagacca tctatcacct tttccccaaa gaagaaacaa aaccagttgc accttaaacc atggatattt tttcctcagg ggctttaaat agtttcctat gcaacgtgtc ttgtagcaca aataaaattc tacaaaagtt gcagtaaatt ttatttggat attttaacct gttaagtgtg tgtgtgtttt ctgtacccaa ccagacttta aataaaacaa acatgaaacc taaaaaaaaa aaa SEQ ID NO: 10 Homo sapiens SH3-domain binding protein 4 (SH3BP4) (NP_055336.1) MAAQRIRAANSNGLPRCKSEGTLIDLSEGFSETSFNDIKVPSPSALLVDNPTPFGNAKEVIAIKDYCPTNFTTLK FSKGDHLYVLDTSGGEWWYAHNTTEMGYIPSSYVQPLNYRNSTLSDSGMIDNLPDSPDEVAKELELLGGWTDDKK VPGRMYSNNPFWNGVQTNPFLNGNVPVMPSLDELNPKSTVDLLLFDAGTSSFTESSSATTNSTGNIFDELPVTNG LHAEPPVRRDNPFFRSKRSYSLSELSVLQAKSDAPTSSSFFTGLKSPAPEQFQSREDFRTAWLNHRKLARSCHDL DLLGQSPGWGQTQAVETNIVCKLDSSGGAVQLPDTSISIHVPEGHVAPGETQQISMKALLDPPLELNSDRSCSIS PVLEVKLSNLEVKTSIILEMKVSAEIKNDLFSKSTVGLQCLRSDSKEGPYVSVPLNCSCGDTVQAQLHNLEPCMY VAVVAHGPSILYPSTVWDFINKKVTVGLYGPKHIHPSFKTVVTIFGHDCAPKTLLVSEVTRQAPNPAPVALQLWG KHQFVLSRPQDLKVCMFSNMTNYEVKASEQAKVVRGFQLKLGKVSRLIFPITSQNPNELSDFTLRVQVKDDQEAI LTQFCVQTPQPPPKSAIKPSGQRRFLKKNEVGKIILSPFATTTKYPTFQDRPVSSLKFGKLLKTVVRQNKNHYLL EYKKGDGIALLSEERVRLRGQLWTKEWYIGYYQGRVGLVHTKNVLVVGRARPSLCSGPELSTSVLLEQILRPCKF LTYIYASVRTLLMENISSWRSFADALGYVNLPLTFFCRAELDSEPERVASVLEKLKEDCNNTENKERKSFQKELV MALLKMDCQGLVVRLIQDFVLLTTAVEVAQRWRELAEKLAKVSKQQMDAYESPHRDRNGVVDSEAMWKPAYDFLL TWSHQIGDSYRDVIQELHLGLDKMKNPITKRWKHLTGTLILVNSLDVLRAAAFSPADQDDFVI SEQ ID NO: 11 Homo sapiens collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant) (COL3A1)(NM_000090) ggctgagttt tatgacgggc ccggtgctga agggcaggga acaacttgat ggtgctactt tgaactgctt ttcttttctc ctttttgcac aaagagtctc atgtctgata tttagacatg atgagctttg tgcaaaaggg gagctggcta cttctcgctc tgcttcatcc cactattatt ttggcacaac aggaagctgt tgaaggagga tgttcccatc ttggtcagtc ctatgcggat agagatgtct ggaagccaga accatgccaa atatgtgtct gtgactcagg atccgttctc tgcgatgaca taatatgtga cgatcaagaa ttagactgcc ccaacccaga aattccattt ggagaatgtt gtgcagtttg cccacagcct ccaactgctc ctactcgccc tcctaatggt caaggacctc aaggccccaa gggagatcca ggccctcctg gtattcctgg gagaaatggt gaccctggta ttccaggaca accagggtcc cctggttctc ctggcccccc tggaatctgt gaatcatgcc ctactggtcc tcagaactat tctccccagt atgattcata tgatgtcaag tctggagtag cagtaggagg actcgcaggc tatcctggac cagctggccc cccaggccct cccggtcccc ctggtacatc tggtcatcct ggttcccctg gatctccagg ataccaagga ccccctggtg aacctgggca agctggtcct tcaggccctc caggacctcc tggtgctata ggtccatctg gtcctgctgg aaaagatgga gaatcaggta gacccggacg acctggagag cgaggattgc ctggacctcc aggtatcaaa ggtccagctg ggatacctgg attccctggt atgaaaggac acagaggctt cgatggacga aatggagaaa agggtgaaac aggtgctcct ggattaaagg gtgaaaatgg tcttccaggc gaaaatggag ctcctggacc catgggtcca agaggggctc ctggtgagcg aggacggcca ggacttcctg gggctgcagg tgctcggggt aatgacggtg ctcgaggcag tgatggtcaa ccaggccctc ctggtcctcc tggaactgcc ggattccctg gatcccctgg tgctaagggt gaagttggac ctgcagggtc tcctggttca aatggtgccc ctggacaaag aggagaacct ggacctcagg gacacgctgg tgctcaaggt cctcctggcc ctcctgggat taatggtagt cctggtggta aaggcgaaat gggtcccgct ggcattcctg gagctcctgg actgatggga gcccggggtc ctccaggacc agccggtgct aatggtgctc ctggactgcg aggtggtgca ggtgagcctg gtaagaatgg tgccaaagga gagcccggac cacgtggtga acgcggtgag gctggtattc caggtgttcc aggagctaaa ggcgaagatg gcaaggatgg atcacctgga gaacctggtg caaatgggct tccaggagct gcaggagaaa ggggtgcccc tgggttccga ggacctgctg gaccaaatgg catcccagga gaaaagggtc ctgctggaga gcgtggtgct ccaggccctg cagggcccag aggagctgct ggagaacctg gcagagatgg cgtccctgga ggtccaggaa tgaggggcat gcccggaagt ccaggaggac caggaagtga tgggaaacca gggcctcccg gaagtcaagg agaaagtggt cgaccaggtc ctcctgggcc atctggtccc cgaggtcagc ctggtgtcat gggcttcccc ggtcctaaag gaaatgatgg tgctcctggt aagaatggag aacgaggtgg ccctggagga cctggccctc agggtcctcc tggaaagaat ggtgaaactg gacctcaggg acccccaggg cctactgggc ctggtggtga caaaggagac acaggacccc ctggtccaca aggattacaa ggcttgcctg gtacaggtgg tcctccagga gaaaatggaa aacctgggga accaggtcca aagggtgatg ccggtgcacc tggagctcca ggaggcaagg gtgatgctgg tgcccctggt gaacgtggac ctcctggatt ggcaggggcc ccaggactta gaggtggagc tggtccccct ggtcccgaag gaggaaaggg tgctgctggt cctcctgggc cacctggtgc tgctggtact cctggtctgc aaggaatgcc tggagaaaga ggaggtcttg gaagtcctgg tccaaagggt gacaagggtg aaccaggcgg tccaggtgct gatggtgtcc cagggaaaga tggcccaagg ggtcctactg gtcctattgg tcctcctggc ccagctggcc agcctggaga taagggtgaa ggtggtgccc ccggacttcc aggtatagct ggacctcgtg gtagccctgg tgagagaggt gaaactggcc ctccaggacc tgctggtttc cctggtgctc ctggacagaa tggtgaacct ggtggtaaag gagaaagagg ggctccgggt gagaaaggtg aaggaggccc tcctggagtt gcaggacccc ctggaggttc tggacctgct ggtcctcctg gtccccaagg tgtcaaaggt gaacgtggca gtcctggtgg acctggtgct gctggcttcc ctggtgctcg tggtcttcct ggtcctcctg gtagtaatgg taacccagga cccccaggtc ccagcggttc tccaggcaag gatgggcccc caggtcctgc gggtaacact ggtgctcctg gcagccctgg agtgtctgga ccaaaaggtg atgctggcca accaggagag aagggatcgc ctggtgccca gggcccacca ggagctccag gcccacttgg gattgctggg atcactggag cacggggtct tgcaggacca ccaggcatgc caggtcctag gggaagccct ggccctcagg gtgtcaaggg tgaaagtggg aaaccaggag ctaacggtct cagtggagaa cgtggtcccc ctggacccca gggtcttcct ggtctggctg gtacagctgg tgaacctgga agagatggaa accctggatc agatggtctt ccaggccgag atggatctcc tggtggcaag ggtgatcgtg gtgaaaatgg ctctcctggt gcccctggcg ctcctggtca tccaggccca cctggtcctg tcggtccagc tggaaagagt ggtgacagag gagaaagtgg ccctgctggc cctgctggtg ctcccggtcc tgctggttcc cgaggtgctc ctggtcctca aggcccacgt ggtgacaaag gtgaaacagg tgaacgtgga gctgctggca tcaaaggaca tcgaggattc cctggtaatc caggtgcccc aggttctcca ggccctgctg gtcagcaggg tgcaatcggc agtccaggac ctgcaggccc cagaggacct gttggaccca gtggacctcc tggcaaagat ggaaccagtg gacatccagg tcccattgga ccaccagggc ctcgaggtaa cagaggtgaa agaggatctg agggctcccc aggccaccca gggcaaccag gccctcctgg acctcctggt gcccctggtc cttgctgtgg tggtgttgga gccgctgcca ttgctgggat tggaggtgaa aaagctggcg gttttgcccc gtattatgga gatgaaccaa tggatttcaa aatcaacacc gatgagatta tgacttcact caagtctgtt aatggacaaa tagaaagcct cattagtcct gatggttctc gtaaaaaccc cgctagaaac tgcagagacc tgaaattctg ccatcctgaa ctcaagagtg gagaatactg ggttgaccct aaccaaggat gcaaattgga tgctatcaag gtattctgta atatggaaac tggggaaaca tgcataagtg ccaatccttt gaatgttcca cggaaacact ggtggacaga ttctagtgct gagaagaaac acgtttggtt tggagagtcc atggatggtg gttttcagtt tagctacggc aatcctgaac ttcctgaaga tgtccttgat gtgcagctgg cattccttcg acttctctcc agccgagctt cccagaacat cacatatcac tgcaaaaata gcattgcata catggatcag gccagtggaa atgtaaagaa ggccctgaag ctgatggggt caaatgaagg tgaattcaag gctgaaggaa atagcaaatt cacctacaca gttctggagg atggttgcac gaaacacact ggggaatgga gcaaaacagt ctttgaatat cgaacacgca aggctgtgag actacctatt gtagatattg caccctatga cattggtggt cctgatcaag aatttggtgt ggacgttggc cctgtttgct ttttataaac caaactctat ctgaaatccc aacaaaaaaa atttaactcc atatgtgttc ctcttgttct aatcttgtca accagtgcaa gtgaccgaca aaattccagt tatttatttc caaaatgttt ggaaacagta taatttgaca aagaaaaatg atacttctct ttttttgctg ttccaccaaa tacaattcaa atgctttttg ttttattttt ttaccaattc caatttcaaa atgtctcaat ggtgctataa taaataaact tcaacactct ttatgataac aacactgtgt tatattcttt gaatcctagc ccatctgcag agcaatgact gtgctcacca gtaaaagata acctttcttt ctgaaatagt caaatacgaa attagaaaag ccctccctat tttaactacc tcaactggtc agaaacacag attgtattct atgagtccca gaagatgaaa aaaattttat acgttgataa aacttataaa tttcattgat taatctcctg gaagattggt ttaaaaagaa aagtgtaatg caagaattta aagaaatatt tttaaagcca caattatttt aatattggat atcaactgct tgtaaaggtg ctcctctttt ttcttgtcat tgctggtcaa gattactaat atttgggaag gctttaaaga cgcatgttat ggtgctaatg tactttcact tttaaactct agatcagaat tgttgacttg cattcagaac ataaatgcac aaaatctgta catgtctccc atcagaaaga ttcattggca tgccacaggg gattctcctc cttcatcctg taaaggtcaa caataaaaac caaattatgg ggctgctttt gtcacactag catagagaat gtgttgaaat ttaactttgt aagcttgtat gtggttgttg atcttttttt tccttacaga cacccataat aaaatatcat attaaaattc SEQ ID NO: 12 Homo sapiens collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant) (COL3A1) (NP_000081.1) MMSFVQKGSWLLLALLHPTIILAQQEAVEGGCSHLGQSYADRDVWKPEPCQICVCDSGSVLCDDIICDDQELDCP NPEIPFGECCAVCPQPPTAPTRPPNGQGPQGPKGDPGPPGIPGRNGDPGIPGQPGSPGSPGPPGICESCPTGPQN YSPQYDSYDVKSGVAVGGLAGYPGPAGPPGPPGPPGTSGHPGSPGSPGYQGPPGEPGQAGPSGPPGPPGAIGPSG PAGKDGESGRPGRPGERGLPGPPGIKGPAGIPGFPGMKGHRGFDGRNGEKGETGAPGLKGENGLPGENGAPGPMG PRGAPGERGRPGLPGAAGARGNDGARGSDGQPGPPGPPGTAGFPGSPGAKGEVGPAGSPGSNGAPGQRGEPGPQG HAGAQGPPGPPGINGSPGGKGEMGPAGIPGAPGLMGARGPPGPAGANGAPGLRGGAGEPGKNGAKGEPGPRGERG EAGIPGVPGAKGEDGKDGSPGEPGANGLPGAAGERGAPGFRGPAGPNGIPGEKGPAGERGAPGPAGPRGAAGEPG RDGVPGGPGMRGMPGSPGGPGSDGKPGPPGSQGESGRPGPPGPSGPRGQPGVMGFPGPKGNDGAPGKNGERGGPG GPGPQGPPGKNGETGPQGPPGPTGPGGDKGDTGPPGPQGLQGLPGTGGPPGENGKPGEPGPKGDAGAPGAPGGKG DAGAPGERGPPGLAGAPGLRGGAGPPGPEGGKGAAGPPGPPGAAGTPGLQGMPGERGGLGSPGPKGDKGEPGGPG ADGVPGKDGPRGPTGPIGPPGPAGQPGDKGEGGAPGLPGIAGPRGSPGERGETGPPGPAGFPGAPGQNGEPGGKG ERGAPGEKGEGGPPGVAGPPGGSGPAGPPGPQGVKGERGSPGGPGAAGFPGARGLPGPPGSNGNPGPPGPSGSPG KDGPPGPAGNTGAPGSPGVSGPKGDAGQPGEKGSPGAQGPPGAPGPLGIAGITGARGLAGPPGMPGPRGSPGPQG VKGESGKPGANGLSGERGPPGPQGLPGLAGTAGEPGRDGNPGSDGLPGRDGSPGGKGDRGENGSPGAPGAPGHPG PPGPVGPAGKSGDRGESGPAGPAGAPGPAGSRGAPGPQGPRGDKGETGERGAAGIKGHRGFPGNPGAPGSPGPAG QQGAIGSPGPAGPRGPVGPSGPPGKDGTSGHPGPIGPPGPRGNRGERGSEGSPGHPGQPGPPGPPGAPGPCCGGV GAAAIAGIGGEKAGGFAPYYGDEPMDFKINTDEIMTSLKSVNGQIESLISPDGSRKNPARNCRDLKFCHPELKSG EYWVDPNQGCKLDAIKVFCNMETGETCISANPLNVPRKHWWTDSSAEKKHVWFGESMDGGFQFSYGNPELPEDVL DVQLAFLRLLSSRASQNITYHCKNSIAYMDQASGNVKKALKLMGSNEGEFKAEGNSKFTYTVLEDGCTKHTGEWS KTVFEYRTRKAVRLPIVDIAPYDIGGPDQEFGVDVGPVCFL SEQ ID NO: 13 Homo sapiens UDP-Gal:betaGlcNAc beta 1,3- galactosyltransferase, polypeptide 2 (B3GALT2) (NM_003783) cctgtgcagc agctgaggaa ccgtggattt catattatag actaaaaccc cattaaaact gctcaaaatc cttcctgcag ctgccaggca acaacgaaag aagagaggta aatcctattc ttttccaata caactgaagc actacatttt agctctggct gctttacatt gcagctcagt gttattagta gaaatatgga tactgagacg agaacacagc actgcattgt ccagccagga aaaatagcag atgtaaaaag cttcaatgca tcaactgtcg ggaagagtca acagtgctac aagcagaacg ggcaactaca gctcttttgt ttaacgaaag agagaatatg aaagaaaggg aaaatttcag aagactagga cccatatgaa caaggagggt aactcgaaga caagcagaca gatggacact ttggatactg tgaaaagcaa tcgcaggagg cagactgttg ggggatgtgc gcatgttcga tagcatcttt tttgctgaag tgatggcgtg ccaaaagtat tttcagtggg cataatcctc ttcacataaa tggcctgacc aaggagaatg actacaagag agacaatgtg actgaattag aaaatgattg ccaaagaata gtattaagga gaagaaaaca tttttgtcac caatctctca tataccacta ctggatattt acaacatgct tcagtggagg agaagacact gctgctttgc aaagatgacc tggaatgcca aaaggtctct gttccgcact catcttattg gagtactttc tctagtgttt ctttttgcta tgtttttgtt tttcaatcat catgactggc tgccaggcag agctggattc aaagaaaacc ctgtgacata cactttccga ggatttcggt caacaaaaag tgagacaaac cacagctccc ttcggaacat ttggaaagaa acagtccctc aaaccctgag gcctcaaaca gcaactaact ctaataacac agacctgtca ccacaaggag ttacaggcct ggagaataca cttagtgcca atggaagtat ttacaatgaa aaaggtactg gacatccaaa ttcttaccat ttcaaatata ttattaatga gcctgaaaaa tgccaagaga aaagtccttt tttaatacta ctaatagctg cagagcctgg acaaatagaa gctagaagag ctattcggca aacttggggc aatgaaagtc tagcacctgg tattcaaatc acaagaatat ttttgttggg cttaagtatt aagctaaatg gctaccttca acgtgcaata ctggaagaaa gcagacaata tcatgatata attcaacagg aatacttaga tacgtactat aatttgacca ttaaaacact aatgggcatg aactgggttg caacatactg tccacatatt ccatatgtta tgaaaactga cagtgacatg tttgtcaaca ctgaatattt aatcaataag ttactgaagc cagatctgcc tcccagacat aactatttca ctggttacct aatgcgagga tatgcaccca atcgaaacaa agatagcaag tggtacatgc caccagacct ctacccaagt gagcgttatc ctgtcttctg ttctggaact ggttatgttt tttctggaga tctggcagaa aagattttta aagtttcttt aggtatccgc cgtttgcact tggaagatgt atatgtaggg atctgtcttg ccaagttgag aattgatcct gtaccccctc ccaatgagtt tgtgttcaat cactggcgag tctcttattc gagctgtaaa tacagccacc taattacctc tcatcagttc cagcctagtg aactgataaa atactggaac catttacaac aaaataagca caatgcctgt gccaacgcag caaaagaaaa ggcaggcagg tatcgccacc gtaaactaca ttagaaaaga caattttttt tcaatgtgca atttgtaaat attgctaaaa gcatgtatag ttaggaactg attacatccg taggacaagt tttagttaaa actcatcaca taaagaaatt caagaagtat ttttttaatt tctgaagaag ttaattctta aaactataac attatataac aaaaaaggtt tcccaaaaca atctatttaa aaaactgtat aaggagattc tgtgtattaa catgcaataa caagcatgca taaatcaatg gttcaagtct tctgttaggg ggccaataaa atgtatctgc atatgttttc cacataaatt ttaattcaag aaatgacagt caaaagatcc ttcattttag attaagcttt tcattttaat atataattta atgtaaataa aacatcacta tcaattttaa ggaaactttt taattgtgca aaggataaat tttttgacct attttagggt tctaaatgca ataagattta gttgagttat tccacaaaca cattataaag ttcagatgtt tcatcaatgc agttctcacg aaagtattta ctttttaaaa ataactgaga tattatttta aatttctttt attaatactt tcttttatta atatatgggg gaaaattatt ttgacatgac gtggtaaaat gtgaaaaact aatgtgtctc aggctcaagt ttttatagtt attaaatgtt tcaaaataga caagttttgt ttcctcattg atgttaagaa ccaaactcct atttcaatga gttattggat tagaccaatt actgcactct taaacagcac caccatttaa tttcatgtaa tatctaactt cgaatatatc tgtaaaggat aatcgaagca aaagtaatca cttaaaggca caaataggat gtactgttga aaaagataaa gagtgcaggt gcagtttcat tcaacacatt tttaagatgc atgtctgcca aaatgcaaca tacgggaagt ttatttcctg acagcaggtg tacacatgcc aacacttaat cattttatgg cacctatttc tttcttggag tgccaagttt gcaaacctgc agtttttaat ttggtagatg acaaatattc tgaatcacca attaaaaacc tttttgggag ggatggggaa aactacaaac gtttgacaaa cacaattcta ggatgaacaa tgtatacaat gcacttttat gaagttttta aaaataaagg aaaacaaaaa acttt SEQ ID NO: 14 Homo sapiens UDP-Gal:betaGlcNAc beta 1,3- galactosyltransferase, polypeptide 2 (B3GALT2) (NP_003774.1) MLQWRRRHCCFAKMTWNAKRSLFRTHLIGVLSLVFLFAMFLFFNHHDWLPGRAGFKENPVTYTFRGFRSTKSETN HSSLRNIWKETVPQTLRPQTATNSNNTDLSPQGVTGLENTLSANGSIYNEKGTGHPNSYHFKYIINEPEKCQEKS PFLILLIAAEPGQIEARRAIRQTWGNESLAPGIQITRIFLLGLSIKLNGYLQRAILEESRQYHDIIQQEYLDTYY NLTIKTLMGMNWVATYCPHIPYVMKTDSDMFVNTEYLINKLLKPDLPPRHNYFTGYLMRGYAPNRNKDSKWYMPP DLYPSERYPVFCSGTGYVFSGDLAEKIFKVSLGIRRLHLEDVYVGICLAKLRIDPVPPPNEFVFNHWRVSYSSCK YSHLITSHQFQPSELIKYWNHLQQNKHNACANAAKEKAGRYRHRKLH SEQ ID NO: 15 Homo sapiens glycosylphosphatidylinositol specific phospholipase D1 (GPLD1)(NM_001503) gtgacctgct tagagagaag cggtgggtct gcacctggat tttggagtcc cagtgctgct gcagctctga gcattcccac gtcaccagag aagccggtgg gcaatgagat catgtctgct ttcaggttgt ggcctggcct gctgatcatg ttgggttctc tctgccatag aggttcaccg tgtggccttt caacacacgt agaaatagga cacagagctc tggagtttct tcagcttcac aatgggcgtg ttaactacag agagctgtta ctagaacacc aggatgcgta tcaggctgga atcgtgtttc ctgattgttt ttaccctagc atctgcaaag gaggaaaatt ccatgatgtg tctgagagca ctcactggac tccgtttctt aatgcaagcg ttcattatat ccgagagaac tatccccttc cctgggagaa ggacacagag aaactggtag ctttcttgtt tggaattact tctcacatgg cggcagatgt cagctggcat agtctgggcc ttgaacaagg attccttagg accatgggag ctattgattt tcacggctcc tattcagagg ctcattcggc tggtgatttt ggaggagatg tgttgagcca gtttgaattt aattttaatt accttgcacg acgctggtat gtgccagtca aagatctact gggaatttat gagaaactgt atggtcgaaa agtcatcacc gaaaatgtaa tcgttgattg ttcacatatc cagttcttag aaatgtatgg tgagatgcta gctgtttcca agttatatcc cacttactct acaaagtccc cgtttttggt ggaacaattc caagagtatt ttcttggagg actggatgat atggcatttt ggtccactaa tatttaccat ctaacaagct tcatgttgga gaatgggacc agtgactgca acctgcctga gaaccctctg ttcattgcat gtggcggcca gcaaaaccac acccagggct caaaaatgca gaaaaatgat tttcacagaa atttgactac atccctaact gaaagtgttg acaggaatat aaactatact gaaagaggag tgttctttag tgtaaattcc tggaccccgg attccatgtc ctttatctac aaggctttgg aaaggaacat aaggacaatg ttcataggtg gctctcagtt gtcacaaaag cacgtctcca gccccttagc atcttacttc ttgtcatttc cttatgcgag gcttggctgg gcaatgacct cagctgacct caaccaggat gggcacggtg acctcgtggt gggcgcacca ggctacagcc gccccggcca catccacatc gggcgcgtgt acctcatcta cggcaatgac ctgggcctgc cacctgttga cctggacctg gacaaggagg cccacaggat ccttgaaggc ttccagccct caggtcggtt tggctcggcc ttggctgtgt tggactttaa cgtggacggc gtgcctgacc tggccgtggg agctccctcg gtgggctccg agcagctcac ctacaaaggt gccgtgtatg tctactttgg ttccaaacaa ggaggaatgt cttcttcccc taacatcacc atttcttgcc aggacatcta ctgtaacttg ggctggactc tcttggctgc agatgtgaat ggagacagtg aacccgatct ggtcatcggc tccccttttg caccaggtgg agggaagcag aagggaattg tggctgcgtt ttattctggc cccagcctga gcgacaaaga aaaactgaac gtggaggcag ccaactggac ggtgagaggc gaggaagact tctcctggtt tggatattcc cttcacggtg tcactgtgga caacagaacc ttgctgttgg ttgggagccc gacctggaag aatgccagca ggctgggcca tttgttacac atccgagatg agaaaaagag ccttgggagg gtgtatggct acttcccacc aaacggccaa agctggttta ccatttctgg agacaaggca atggggaaac tgggtacttc cctttccagt ggccacgtac tgatgaatgg gactctgaaa caagtgctgc tggttggagc ccctacgtac gatgacgtgt ctaaggtggc attcctgacc gtgaccctac accaaggcgg agccactcgc atgtacgcac tcacatctga cgcgcagcct ctgctgctca gcaccttcag cggagaccgc cgcttctccc gatttggtgg cgttctgcac ttgagtgacc tggatgatga tggcttagat gaaatcatca tggcagcccc cctgaggata gcagatgtaa cctctggact gattggggga gaagacggcc gagtatatgt atataatggc aaagagacca cccttggtga catgactggc aaatgcaaat catggataac tccatgtcca gaagaaaagg cccaatatgt attgatttct cctgaagcca gctcaaggtt tgggagctcc ctcatcaccg tgaggtccaa ggcaaagaac caagtcgtca ttgctgctgg aaggagttct ttgggagccc gactctccgg ggcacttcac gtctatagcc ttggctcaga ttgaagattt cactgcattt ccccactctg cccacctctc tcatgctgaa tcacatccat ggtgagcatt ttgatggaca aagtggcaca tccagtggag cggtggtaga tcctgataga catggggctc ctgggagtag agagacacac taacagccac accctctgga aatctgatac agtaaatata tgactgcacc agaaatatgt gaaatagcag acattctgct tactcatgtc tccttccaca gtttacttcc tcgctccctt tgcatctaaa cctttcttct ttcccaactt attgcctgta gtcagacctg ctgtacaacc tatttcctct tcctcttgaa tgtctttcca atggctggaa aggtccctct gtggttatct gttagaacag tctctgtaca caattcctcc taaaaacatc cttttttaaa aaaagaattg ttcagccata aagaaagaac aagatcatgc cctttgcagg gacatggatg gagctggagg ccattatcct tcataaacta ttgcaggaac agaaaaccaa acactccata ttctcacttg taagtgggag ctaaatgaga acacgtggac acatagaggg aaacaacaca cactggggcc tatgagaggg cggaaggtgg gaggagggag agatcaggaa aaataactaa tggatactta gggtgatgaa ataatctgtg taacaaaccc ccatgacaca cctttatgta tgtaacaaac cagcacttcc tgcgcatgta cccctgaact taaaagttaa aaaaaagttg aacttaaaaa taacagattg gcccatgcca atcaaagtat aatagaaagc atagtatac SEQ ID NO: 16 Homo sapiens glycosylphosphatidylinositol specific phospholipase D1 (GPLD1)(NP_001494.2) MSAFRLWPGLLIMLGSLCHRGSPCGLSTHVEIGHRALEFLQLHNGRVNYRELLLEHQDAYQAGIVFPDCFYPSIC KGGKFHDVSESTHWTPFLNASVHYIRENYPLPWEKDTEKLVAFLFGITSHMAADVSWHSLGLEQGFLRTMGAIDF HGSYSEAHSAGDFGGDVLSQFEFNFNYLARRWYVPVKDLLGIYEKLYGRKVITENVIVDCSHIQFLEMYGEMLAV SKLYPTYSTKSPFLVEQFQEYFLGGLDDMAFWSTNIYHLTSFMLENGTSDCNLPENPLFIACGGQQNHTQGSKMQ KNDFHRNLTTSLTESVDRNINYTERGVFFSVNSWTPDSMSFIYKALERNIRTMFIGGSQLSQKHVSSPLASYFLS FPYARLGWAMTSADLNQDGHGDLVVGAPGYSRPGHIHIGRVYLIYGNDLGLPPVDLDLDKEAHRILEGFQPSGRF GSALAVLDFNVDGVPDLAVGAPSVGSEQLTYKGAVYVYFGSKQGGMSSSPNITISCQDIYCNLGWTLLAADVNGD SEPDLVIGSPFAPGGGKQKGIVAAFYSGPSLSDKEKLNVEAANWTVRGEEDFSWFGYSLHGVTVDNRTLLLVGSP TWKNASRLGHLLHIRDEKKSLGRVYGYFPPNGQSWFTISGDKAMGKLGTSLSSGHVLMNGTLKQVLLVGAPTYDD VSKVAFLTVTLHQGGATRMYALTSDAQPLLLSTFSGDRRFSRFGGVLHLSDLDDDGLDEIIMAAPLRIADVTSGL IGGEDGRVYVYNGKETTLGDMTGKCKSWITPCPEEKAQYVLISPEASSRFGSSLITVRSKAKNQVVIAAGRSSLG ARLSGALHVYSLGSD SEQ ID NO: 17 Homo sapiens myotubularin related protein 7 (MTMR7)(NM_004686) gcgcccgccc gggaccctgc agacgtgggc cagccatgga gcacatccgc acgcccaagg ttgaaaatgt ccgcttggta gatcgagtgt ctcctaaaaa agcagctcta ggtactttgt atttgacggc tacccatgtc atattcgtgg aaaattcacc tgacgcaaga aaagaaacat ggattcttca cagtcagatt tccaccattg agaaacaggc aacaaccgct accggatgcc ctctgctgat tcgctgcaag aactttcaga taatacagct catcatacct caggaaagag attgccacga cgtgtacatc tccctgatac gccttgcaag gccagtgaaa tatgaggagt tatactgctt ttcattcaac cccatgctgg ataaagaaga aagagagcaa ggctgggtgc tgatcgatct tagtgaagaa tacacgcgga tgggcctccc taatcattac tggcagctca gcgatgtgaa tagagactac agagtctgtg actcttatcc tactgaactg tacgttccca aatcggccac ggcacacatc atagtgggga gttccaaatt ccggagtaga cggcgatttc ctgtcctttc ttactattat aaagataacc acgcctccat ctgccggagc agccagcccc tgtccggctt cagtgcccgg tgcctggagg acgagcagat gctccaggcc attaggaaag ccaatccagg aagtgacttc gtttatgtcg ttgacgcccg gcctaaactt aatgcaatgg caaatcgtgc tgcagggaaa ggctatgaga atgaagacaa ttattccaat atcaagtttc agtttatcgg gatagagaac atccatgtca tgaggaacag tctgcagaaa atgctggaag tgtgtgaact taaatctccc tccatgagtg atttcctgtg gggtctggag aactctggct ggttaaggca cattaaagcc ataatggatg caggaatctt cattgcaaag gcagtgtcag aggaaggggc aagtgtgctt gttcactgtt ctgatggctg ggacaggacc gctcaggtgt gctcggtggc aagcctgctg ctggaccctc actaccggac tctgaagggc ttcatggtat taattgaaaa ggactggatt tcctttggtc ataagtttaa tcaccgatat ggcaatctag atggtgaccc aaaagaaatc tctccagtta ttgaccagtt cattgagtgt gtttggcagt taatggaaca atttccctgt gcctttgagt tcaatgagag gtttttgatt cacattcaac atcacattta ttcctgccag tttggaaact tcctatgtaa cagccaaaag gagagacgag aactcaagat tcaagaaaga acatactcat tatgggctca cctgtggaag aatcgggccg actacctgaa tcctctgttt agagctgatc acagccagac tcagggaacc cttcatctcc ctacaacacc atgtaacttc atgtacaagt tttggagtgg aatgtataac cgctttgaaa aggggatgca gccccgacag tcagttacag attacctaat ggcagtgaag gaagaaactc agcagctaga ggaagaacta gaggccctgg aagaaaggct ggaaaaaatt caaaaggtcc agttaaattg cactaaggtg aagagtaagc aaagtgagcc cagcaagcac tcagggtttt ctacctcaga caacagcata gccaacactc cccaggatta cagtgggaat atgaaatcat ttccatcccg gagcccttca caaggcgatg aagattctgc tctgattcta acccaagaca atctgaaaag ttcagatcca gatctgtcag ccaacagtga ccaagagtcc ggggtggagg atttgagctg tcggtctcca agtggtggtg agcatgcacc gagtgaagat agtggcaagg accgggattc tgatgaagcc gtgtttctca ctgcctgaag tttccctttg gagttccaaa gtaaaggaca cataagcaac acttccaaaa acaagggaac aaggtggttt attgtaaaaa caggaaatgg tgcatgtcat tgagaactat tttaatgcag ctatgaaaag ggaaaaaagt gcccagttct tgatttctta gatactgaag aggacgtagt catttcattt atcaaatata aggaaaatta ttcaccattt tgaagctcac cctagactat gaaaattata ttcactgcag agcaattact tctgtcatta cctgaagtga tcagtatcta tcttccttgt catagcatgc atctctcaaa aagcctccac tcctttccct cacatctgtg atcatcatga ttcttttagt tcacttctag atgcatattt tgtgttttct aaagcatctg acattatcct cctttccgac cctcttatac atatttctaa aaacaggcac attggtgaga tgcacccttt ttagttaata gatgcattcc taaggagctt ttaattgctt atctttcagg cataatcatc actttaactt ttccttggag catatatttt gaattgtgag aataattttg ttgcttttct ctgagatcta tagtctgttt ctcctcatta tttaaaaatg ctaaaccttg tatctcactt tttctctaac actgatttaa tagctaacga ggtagaagca acattcattc tcctggtctt acatatgaat ttaagtatca gctttcttgt aataaccttt tattactgtt ctagagacta cactaccgac agtgtgggcc agccaccagc ctgatctcaa agtatcacat tataaagtta gtagataaaa catctgtgag tgaaaatcca gtttcaggaa ccagagaatt gggttgtcat gtctgtttaa tgaagggaat aggttttgta atctatcatt ttagaaatta tgtaactggc taatatggtt taattaacct tagtaacatc tcgtgaccac tgactgctga aagttctgaa aagaattttt gttttgttac actgcacatt taagggagag tccctcccct atcttatgag ttaaaaaaga cttcactagg tgacctaaat taaacttagt ggggaaaagt ggccatgttt ggacataaat aaatggtatt cacactgtat ggttttaata tattagtaca ttctagaatg taaaaggatt aaactttaca atttagatca atattttgaa tatgtgaaag gattaattta aactttacaa tttacatcaa tattttgaat atctgatttt ttttaatggg agaattatta catttcgctg aaatgaggac gagggcaaga aagcaacatt gctgatctct ctagtatgaa agatttggag ggagtgttgc aatatatata aatgaaaaca tttaattgtg ttcatcatat ttaaaaatat agaatatatt agagaactgt gatttaaaag tactgttaat gtaaaaaata aagcaagtgt aattaattct ttcagaatat aaaatttggg cattctctgc tgagcagttc ccaaattaag tacaaggaat gtttattcat tttctgcaat atactatatg taatagggaa taccttgcta aaataaaact taggatatag tggtaatggc tttcacattt ttataacata acataactca cttcacaacc ttcttggagc tgtccactct tagaaactct gttgcctaat attgaggatg tggctttaat ttcttccgtt tgacagtgta tgtctataaa aacaataaac attttttaaa aaatgacaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aa SEQ ID NO: 18 Homo sapiens myotubularin related protein 7 (MTMR7)(NP_004677.2) MEHIRTPKVENVRLVDRVSPKKAALGTLYLTATHVIFVENSPDARKETWILHSQISTIEKQATTATGCPLLIRCK NFQIIQLIIPQERDCHDVYISLIRLARPVKYEELYCFSFNPMLDKEEREQGWVLIDLSEEYTRMGLPNHYWQLSD VNRDYRVCDSYPTELYVPKSATAHIIVGSSKFRSRRRFPVLSYYYKDNHASICRSSQPLSGFSARCLEDEQMLQA IRKANPGSDFVYVVDARPKLNAMANRAAGKGYENEDNYSNIKFQFIGIENIHVMRNSLQKMLEVCELKSPSMSDF LWGLENSGWLRHIKAIMDAGIFIAKAVSEEGASVLVHCSDGWDRTAQVCSVASLLLDPHYRTLKGFMVLIEKDWI SFGHKFNHRYGNLDGDPKEISPVIDQFIECVWQLMEQFPCAFEFNERFLIHIQHHIYSCQFGNFLCNSQKERREL KIQERTYSLWAHLWKNRADYLNPLFRADHSQTQGTLHLPTTPCNFMYKFWSGMYNRFEKGMQPRQSVTDYLMAVK EETQQLEEELEALEERLEKIQKVQLNCTKVKSKQSEPSKHSGFSTSDNSIANTPQDYSGNMKSFPSRSPSQGDED SALILTQDNLKSSDPDLSANSDQESGVEDLSCRSPSGGEHAPSEDSGKDRDSDEAVFLTA SEQ ID NO: 19 Homo sapiens transmembrane protein with EGF-like and two follistatin-like domains 1 (TMEFF1)(NM_003692) agcgggcggc tgctaggagg caccgaggca gcggcggggc tctgggcgcg cggctggatg cccccggcct gcggctccct gcgcttcccg ccgtccaggg gcaccagtca tgggcgccgc agccgctgag gcgccgctcc ggctgcctgc cgcgcctccg ctcgccttct gctgctacac gtcggtgctt ctgctcttcg ccttctctct gccagggagc cgcgcgtcca accagccccc gggtggtggc ggcggcagcg gcggggactg tcccggcggc aaaggcaaga gcatcaactg ctcagaatta aatgtgaggg agtctgacgt aagagtttgt gatgagtcat catgtaaata tggaggagtc tgtaaagaag atggagatgg tttgaaatgt gcatgccaat ttcagtgcca tacaaattat attcctgtct gtggatcaaa tggggacact tatcaaaatg aatgctttct cagaagggct gcttgtaagc accagaaaga gataacagta atagcaagag gaccatgcta ctctgataat ggatctggat ctggagaagg agaagaggaa gggtcagggg cagaagttca cagaaaacac tccaagtgtg gaccctgcaa atataaagct gagtgtgatg aagatgcaga aaatgttggg tgtgtatgta atatagattg cagtggatac agttttaatc ctgtgtgtgc ttctgatggg agttcctata acaatccctg ttttgttcga gaagcatctt gtataaagca agaacaaatt gatataaggc atcttggtca ttgcacagat acagatgaca ctagtttgtt gggaaagaaa gatgatggac tacaatatcg accagatgtg aaagatgcta gtgatcaaag agaagatgtt tatattggaa accacatgcc ttgccctgaa aacctcaatg gttactgcat ccatggaaaa tgtgaattca tctattctac tcagaaggct tcttgtagat gtgaatctgg ctacactgga cagcactgtg aaaagacaga ctttagtatt ctctatgtag tgccaagtag gcaaaagctc actcatgttc ttattgcagc aattattgga gctgtacaga ttgccatcat agtagcaatt gtaatgtgca taacaagaaa atgccccaaa aacaatagag gacgtcgaca gaagcaaaac ctaggtcatt ttacttcaga tacgtcatcc agaatggttt aaactgatga cttttatatg tacactgacc atgtgatgta catttattat gtcttttttt aaagaatgga aatatttatt tcagaggcct tatttttgga catttttagt gtagtactgt tggctcgtat ttagaatatt cagctacgac agttttggac tctttagtag tctttgtttt atgtttttaa atacagaaat tgctttcaca aatttgtacc acatggtaat tctaagactt gttctttacc catggaatgt aatatttttg caaagatgga ctacttcaca aatggttata aagtcatatc cacttcttcc acaatgacca cagcaaatga ccaagcatga actaaaggta aagatgttta cagattactt ttcttacaaa aaaatctaga agacactgtg tttaaataga tatttaaatg tttttgagat ttagtaactg attttttaga cactgcctat cgcatgaact gtaaagctgt gtgtattagg tgtaaaatat ttataagata tatggactgg ggaatttgat tattcctccc tttgaaaaaa tagtcctaat aatttgaaca aatatgttag taatgatgga acagatcaat gaaaagtaga tatagatatt gtgaaaatag gctgtttaac aaacagattg gaataaagcc tattctacca gttaaactac tttaatacac attcattttt aaagaaaatg tttgttttaa cataaataaa caaatcgtat cagtgtttgt gaataaaata caaaaatgat tgttaatgat tggtgctctt aaagtgagct taaaatttat ccaagacgta tatccaaatt tgtcctgtag taatagatta atattcatag attgttggtg tttaaagatc tgaagtgtga gtagaatgta ttcagctgtt taacatgtag tttagatatt caaaagtatg catgtagaat ttaaagaata tgttaaaaat tattaatctt aatattttgt ttggaaaagc atgttataat ataatgtttt cacaaaaaaa aaaaaaaaa SEQ ID NO: 20 Homo sapiens transmembrane protein with EGF-like and two follistatin-like domains 1 (TMEFF1)(NP_003683.2) MGAAAAEAPLRLPAAPPLAFCCYTSVLLLFAFSLPGSRASNQPPGGGGGSGGDCPGGKGKSINCSELNVRESDVR VCDESSCKYGGVCKEDGDGLKCACQFQCHTNYIPVCGSNGDTYQNECFLRRAACKHQKEITVIARGPCYSDNGSG SGEGEEEGSGAEVHRKHSKCGPCKYKAECDEDAENVGCVCNIDCSGYSFNPVCASDGSSYNNPCFVREASCIKQE QIDIRHLGHCTDTDDTSLLGKKDDGLQYRPDVKDASDQREDVYIGNHMPCPENLNGYCIHGKCEFIYSTQKASCR CESGYTGQHCEKTDFSILYVVPSRQKLTHVLIAAIIGAVQIAIIVAIVMCITRKCPKNNRGRRQKQNLGHFTSDT SSRMV SEQ ID NO: 21 Homo sapiens NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 5, 13 kDa (NDUFA5), nuclear gene encoding mitochondrial protein (NM_005000) tggagctaag ctgtttccag ggtgacagag tggcgacctc ggtggtcgat tgagcaggtc tgagaattgt tcccaaaggg ttgtgcgtca ccgagtcgtt ggcgctgtca tggcgggtgt gctgaagaag accactggcc ttgtgggatt ggctgtgtgc aatactcctc acgagaggct aagaatattg tacacaaaga ttcttgatgt tcttgaggaa atccctaaaa atgcagcata tagaaagtat acagaacaga ttacaaatga gaagctggct atggttaaag cggaaccaga tgttaaaaaa ttagaagacc aacttcaagg cggtcaatta gaagaggtga ttcttcaggc tgaacatgaa ctaaatctgg caagaaaaat gagggaatgg aaactatggg agccattagt ggaagagcct cctgccgatc agtggaaatg gccaatataa ttattaagtg actttggtgt gttcatggga aactgatgta attaaatatt ctgttatatt aagagcgtgt tcttattact gacattttgt aatcaagaaa agtgatatag aaaatatgta ggagactgtt aaaattggtg attatggtaa tatggtcatg tgaatcaatt tttgatttat aaagtactca cacaagttgt ttcaaagatg atatttctgt gaacagagag gccatgggaa gatttgaaaa ttattaaaga aaaattccta cagattttca atgcagagac cataatcaaa aagtaaactt tctttagtag tatgttcaat acatcattta attttttaag ttatcctgaa gaaggaaagg tccttaatta ttatagtcta aacaaattta tagattactg tttgaagtaa ataatacgag tgaatatttt caaatgtgat aaaatagcac aagtggctgg tgataaaatt tgaaattatg gttaacctca gctgtgatct tatgtatgta aagtgaaatt taaatagata attataggtt gattacaaaa tccatagtgt cattttattt tagtcattat tgaattatac catttactct gttttcttat agtcttaatt ttattatatt ttgttgttac tgtattatat ttgaaaacct tcaaattaga atacattgta cagttaaaga aattgacttg gtacttaaaa gaaagatttc ccattgcata caggttattg gagaaatttt ccttttgttg catttgtgga agttagtttt ctggcccgtg gcctttaatt ttcttaatca acctaattac atcaggatag aggtagagtt tctgtaaaag aagagacatt aagagttcct gaaatttata tctggcatac cgataggctt atattcaaaa catcttagtc atacgaccat aaattaaaag tggagtcact aaatagtttg cagtacgttt ctaatataag tgtaggtggg tatcaaaaca agacaaatgc tgttcaggga aagaagttgg caagcttaag gttaaacaaa aataaaatta catgtgtttt cgccttccta SEQ ID NO: 22 Homo sapiens NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 5, 13 kDa (NDUFA5), nuclear gene encoding mitochondrial protein (NP_004991.1) MAGVLKKTTGLVGLAVCNTPHERLRILYTKILDVLEEIPKNAAYRKYTEQITNEKLAMVKAEPDVKKLEDQLQGG QLEEVILQAEHELNLARKMREWKLWEP LVEEPPADQWKWPI SEQ ID NO: 23 Homo sapiens FAT tumor suppressor homolog 2 (Drosophila) (FAT2) (NM_001447) ggagttttcc accatgacta ttgccctgct gggttttgcc atattcttgc tccattgtgc gacctgtgag aagcctctag aagggattct ctcctcctct gcttggcact tcacacactc ccattacaat gccaccatct atgaaaattc ttctcccaag acctatgtgg agagcttcga gaaaatgggc atctacctcg cggagccaca gtgggcagtg aggtaccgga tcatctctgg ggatgtggcc aatgtattta aaactgagga gtatgtggtg ggcaacttct gcttcctaag aataaggaca aagagcagca acacagctct tctgaacaga gaggtgcgag acagctacac cctcatcatc caagccacag agaagacctt ggagttggaa gctttgaccc gtgtggtggt ccacatcctg gaccagaatg acctgaagcc tctcttctct ccaccttcgt acagagtcac catctctgag gacatgcccc tgaagagccc catctgcaag gtgactgcca cagatgctga tctaggccag aatgctgagt tctattatgc ctttaacaca aggtcagaga tgtttgccat ccatcccacc agcggtgtgg tcactgtggc tgggaagctt aacgtcacct ggcgaggaaa gcatgagctc caggtgctag ctgtggaccg catgcggaaa atctctgagg gcaatgggtt tggcagcctg gctgcacttg tggttcatgt ggagcctgcc ctcaggaagc ccccagccat tgcttcggtg gtggtgactc caccagacag caatgatggt accacctatg ccactgtact ggtcgatgca aatagctcag gagctgaagt ggagtcagtg gaagttgttg gtggtgaccc tggaaagcac ttcaaagcca tcaagtctta tgcccggagc aatgagttca gtttggtgtc tgtcaaagac atcaactgga tggagtacct tcatgggttc aacctcagcc tccaggccag gagtgggagc ggcccttatt tttattccca gatcaggggc tttcacctac caccttccaa actgtcttcc ctcaaattcg agaaggctgt ttacagagtg cagcttagtg agttttcccc tcctggcagc cgcgtggtga tggtgagagt caccccagcc ttccccaacc tgcagtatgt tctaaagcca tcttcagaga atgtaggatt taaacttaat gctcgaactg ggttgatcac caccacaaag ctcatggact tccacgacag agcccactat cagctacaca tcagaacctc accgggccag gcctccaccg tggtggtcat tgacattgtg gactgcaaca accatgcccc cctcttcaac aggtcttcct atgatggtac cttggatgag aacatccctc caggcaccag tgttttggct gtgactgcca ctgaccggga tcatggggaa aatggatatg tcacctattc cattgctgga ccaaaagctt tgccattttc tattgacccc tacctgggga tcatctccac ctccaaaccc atggactatg aactcatgaa aagaatttat accttccggg taagagcatc agactgggga tccccttttc gccgggagaa ggaagtgtcc atttttcttc agctcaggaa cttgaatgac aaccagccta tgtttgaaga agtcaactgt acagggtcta tccgccaaga ctggccagta gggaaatcga taatgactat gtcagccata gatgtggatg agcttcagaa cctaaaatac gagattgtat caggcaatga actagagtat tttgatctaa atcatttctc cggagtgata tccctcaaac gcccttttat caatcttact gctggtcaac ccaccagtta ttccctgaag attacagcct cagatggcaa aaactatgcc tcacccacaa ctttgaatat tactgtggtg aaggaccctc attttgaagt tcctgtaaca tgtgataaaa caggggtatt gacacaattc acaaagacta tcctccactt tattgggctt cagaaccagg agtccagtga tgaggaattc acttctttaa gcacatatca gattaatcat tacaccccac agtttgagga ccacttcccc caatccattg atgtccttga gagtgtccct atcaacaccc ccttggcccg cctagcagcc actgaccctg atgctggttt taatggcaaa ctggtctatg tgattgcaga tggcaatgag gagggctgct ttgacataga gctggagaca gggctgctca ctgtagctgc tcccttggac tatgaagcca ccaatttcta catcctcaat gtaacagtat atgacctggg cacaccccag aagtcctcct ggaagctgct gacagtgaat gtgaaagact ggaatgacaa cgcacccaga tttcctcccg gtgggtacca gttaaccatc tcggaggaca cagaagttgg aaccacaatt gcagagctga caaccaaaga tgctgactcg gaagacaatg gcagggttcg ctacaccctg ctaagtccca cagagaagtt ctccctccac cctctcactg gggaactggt tgttacagga cacctggacc gcgaatcaga gcctcggtac atactcaagg tggaggccag ggatcagccc agcaaaggcc accagctctt ctctgtcact gacctgataa tcacattgga ggatgtcaac gacaactctc cccagtgcat cacagaacac aacaggctga aggttccaga ggacctgccc cccgggactg tcttgacatt tctggatgcc tctgatcctg acctgggccc cgcaggtgaa gtgcgatatg ttctgatgga tggcgcccat gggaccttcc gggtggacct gatgacaggg gcgctcattc tggagagaga gctggacttt gagaggcgag ctgggtacaa tctgagcctg tgggccagtg atggtgggag gcccctagcc cgcaggactc tctgccatgt ggaggtgatc gtcctggatg tgaatgagaa tctccaccct ccccactttg cctccttcgt gcaccagggc caggtgcagg agaacagccc ctcgggaact caggtgattg tagtggctgc ccaggacgat gacagtggct tggatgggga gctccagtac ttcctgcgtg ctggcactgg actcgcagcc ttcagcatca accaagatac aggaatgatt cagactctgg cacccctgga ccgagaattt gcatcttact actggttgac ggtattagca gtggacaggg gttctgtgcc cctctcttct gtaactgaag tctacatcga ggttacggat gccaatgaca acccacccca gatgtcccaa gctgtgttct acccctccat ccaggaggat gctcccgtgg gcacctctgt gcttcaactg gatgcctggg acccagactc cagctccaaa gggaagctga ccttcaacat caccagtggg aactacatgg gattctttat gattcaccct gttacaggtc tcctatctac agcccagcag ctggacagag agaacaagga tgaacacatc ctggaggtga ctgtgctgga caatggggaa ccctcactga agtccacctc cagggtggtg gtaggcatct tggacgtcaa tgacaatcca cctatattct cccacaagct cttcaatgtc cgccttccag agaggctgag ccctgtgtcc cctgggcctg tgtacaggct ggtggcttca gacctggatg agggtcttaa tggcagagtc acctacagta tcgaggacag cgatgaggag gccttcagta tcgacctggt cacaggtgtg gtttcatcca gcagcacttt tacagctgga gagtacaaca tcctaacgat caaggcaaca gacagtgggc agccaccact ctcagccagt gtccggctac acattgagtg gatcccttgg ccccggccgt cctccatccc tctggccttt gatgagacct actacagctt tacggtcatg gagacggacc ctgtgaacca catggtgggg gtcatcagcg tagagggcag acccggactc ttctggttca acatctcagg tggggataag gacatggact ttgacattga gaagaccaca ggcagcatcg tcattgccag gcctcttgat accaggagaa ggtcgaacta taacttgact gttgaggtga cagatgggtc ccgcaccatt gccacacagg tccacatctt catgattgcc aacattaacc accatcggcc ccagtttctg gaaactcgtt atgaagtcag agttccccag gacaccgtgc caggggtaga gctcctgcga gtccaggcca tagatcaaga caagggcaaa agcctcatct ataccataca tggcagccaa gacccaggaa gtgccagcct cttccagctg gacccaagca gtggtgtcct ggtaacggtg ggaaaattgg acctcggctc ggggccctcc cagcacacac tgacagtcat ggtccgagac caggaaatac ctatcaagag gaacttcgtg tgggtgacca ttcatgtgga ggatggaaac ctccacccac cccgcttcac tcagctccat tatgaggcaa gtgttcctga caccatagcc cccggcacag agctgctgca ggtccgagcc atggatgctg accggggagt caatgctgag gtccactact ccctcctgaa agggaacagc gaaggtttct tcaacatcaa tgccctgcta ggcatcatta ctctagctca aaagcttgat caggcaaatc atgccccaca tactctgaca gtgaaggcag aagatcaagg ctccccacaa tggcatgacc tggctacagt gatcattcat gtctatccct cagataggag tgcccccatc ttttcaaaat ctgagtactt tgtagagatc cctgaatcaa tccctgttgg ttccccaatc ctccttgtct ctgctatgag cccctctgaa gttacctatg agttaagaga gggaaataag gatggagtct tctctatgaa ctcatattct ggccttattt ccacccagaa gaaattggac catgagaaaa tctcgtctta ccagctgaaa atccgaggca gcaatatggc aggtgcattt actgatgtca tggtggtggt tgacataatt gatgaaaatg acaatgctcc tatgttctta aagtcaactt ttgtgggcca aattagtgaa gcagctccac tgtatagcat gatcatggat aaaaacaaca acccctttgt gattcatgcc tctgacagtg acaaagaagc taattccttg ttggtctata aaattttgga gccggaggcc ttgaagtttt tcaaaattga tcccagcatg ggaaccctaa ccattgtatc agagatggat tatgagagca tgccctcttt ccaattctgt gtctatgtcc atgaccaagg aagccctgta ttatttgcac ccagacctgc ccaagtcatc attcatgtca gagatgtgaa tgattcccct cccagattct cagaacagat atatgaggta gcaatagtcg ggcctatcca tccaggcatg gagcttctca tggtgcgggc cagcgatgaa gactcagaag tcaattatag catcaaaact ggcaatgctg atgaagctgt taccatccat cctgtcactg gtagcatatc tgtgctgaat cctgctttcc tgggactctc tcggaagctc accatcaggg cttctgatgg cttgtatcaa gacactgcgc tggtaaaaat ttctttgacc caagtgcttg acaaaagctt gcagtttgat caggatgtct actgggcagc tgtgaaggag aacttgcagg acagaaaggc actggtgatt cttggtgccc agggcaatca tttgaatgac accctttcct actttctctt gaatggcaca gatatgtttc atatggtcca gtcagcaggt gtgttgcaga caagaggtgt ggcgtttgac cgggagcagc aggacactca tgagttggca gtggaagtga gggacaatcg gacacctcag cgggtggctc agggtttggt cagagtctct attgaggatg tcaatgacaa tccccccaaa tttaagcatc tgccctatta cacaatcatc caagatggca cagagccagg ggatgtcctc tttcaggtat ctgccactga tgaggacttg gggacaaatg gggctgttac atatgaattt gcagaagatt acacatattt ccgaattgac ccctatcttg gggacatatc actcaagaaa ccctttgatt atcaagcttt aaataaatat cacctcaaag tcattgctcg ggatggagga acgccatccc tccagagtga ggaagaggta cttgtcactg tgagaaataa atccaaccca ctgtttcaga gtccttatta caaagtcaga gtacctgaaa atatcaccct ctatacccca attctccaca cccaggcccg gagtccagag ggactccggc tcatctacaa cattgtggag gaagaaccct tgatgctgtt caccactgac ttcaagactg gtgtcctaac agtaacaggg cctttggact atgagtccaa gaccaaacat gtgttcacag tcagagccac ggatacagct ctggggtcat tttctgaagc cacagtggaa gtcctagtgg aggatgtcaa tgataaccct cccacttttt cccaattggt ctataccact tccatctcag aaggcttgcc tgctcagacc cctgtgatcc aactgttggc ttctgaccag gactcagggc ggaaccgtga cgtctcttat cagattgtgg aggatggctc agatgtttcc aagttcttcc agatcaatgg gagcacaggg gagatgtcca cagttcaaga actggattat gaagcccaac aacactttca tgtgaaagtc agggccatgg ataaaggaga tcccccactc actggtgaaa cccttgtggt tgtcaatgtg tctgatatca atgacaaccc cccagagttc agacaacctc aatatgaagc caatgtcagt gaactggcaa cctgtggaca cctggttctt aaagtccagg ctattgaccc tgacagcaga gacacctccc gcctggagta cctgattctt tctggcaatc aggacaggca cttcttcatt aacagctcat cgggaataat ttctatgttc aacctttgca aaaagcacct ggactcttct tacaatttga gggtaggtgc ttctgatgga gtcttccgag caactgtgcc tgtgtacatc aacactacaa atgccaacaa gtacagccca gagttccagc agcaccttta tgaggcagaa ttagcagaga atgcaatggt tggaaccaag gtgattgatt tgctagccat agacaaagat agtggtccct atggcactat agattatact atcatcaata aactagcaag tgagaagttc tccataaacc ccaatggcca gattgccact ctgcagaaac tggatcggga aaattcaaca gagagagtca ttgctattaa ggtcatggct cgggatggag gaggaagagt agccttctgc acggtgaaga tcatcctcac agatgaaaat gacaaccccc cacagttcaa agcatctgag tacacagtat ccattcaatc caatgtcagt aaagactctc cggttatcca ggtgttggcc tatgatgcag atgaaggtca gaacgcagat gtcacctact cagtgaaccc agaggaccta gttaaagatg tcattgaaat taacccagtc actggtgtgg tcaaggtgaa agacagcctg gtgggattgg aaaatcagac ccttgacttc ttcatcaaag cccaagatgg aggccctcct cactggaact ctctggtgcc agtacgactt caggtggttc ctaaaaaagt atccttaccg aaattttctg aacctttgta tactttctct gcacctgaag accttccaga ggggtctgaa attgggattg ttaaagcagt ggcagctcaa gatccagtca tctacagtct agtgcggggc actacacctg agagcaacaa ggatggtgtc ttctccctag acccagacac aggggtcata aaggtgagga agcccatgga ccacgaatcc accaaattgt accagattga tgtgatggca cattgccttc agaacactga tgtggtgtcc ttggtctctg tcaacatcca agtgggagac gtcaatgaca ataggcctgt atttgaggct gatccatata aggctgtcct cactgagaat atgccagtgg ggacctcagt cattcaagtg actgccattg acaaggacac tgggagagat ggccaggtga gctacaggct gtctgcagac cctggtagca atgtccatga gctctttgcc attgacagtg agagtggttg gatcaccaca ctccaggaac ttgactgtga gacctgccag acttatcatt ttcatgtggt ggcctatgac cacggacaga ccatccagct atcctctcag gccctggttc aggtctccat tacagatgag aatgacaatg ctccccgatt tgcttctgaa gagtacagag gatctgtggt tgagaacagt gagcctggcg aactggtggc gactctaaag accctggatg ctgacatttc tgagcagaac aggcaggtca cctgctacat cacagaggga gaccccctgg gccagtttgg catcagccaa gttggagatg agtggaggat ttcctcaagg aagaccctgg accgcgagca tacagccaag tacttgctca gagtcacagc atctgatggc aagttccagg cttcggtcac tgtggagatc tttgtcctgg acgtcaatga taacagccca cagtgttcac agcttctcta tactggcaag gttcatgaag atgtatttcc aggacacttc attttgaagg tttctgccac agacttggac actgatacca atgctcagat cacatattct ctgcatggcc ctggggcgca tgaattcaag ctggatcctc atacagggga gctgaccaca ctcactgccc tagaccgaga aaggaaggat gtgttcaacc ttgttgccaa ggcgacggat ggaggtggcc gatcgtgcca ggcagacatc accctccatg tggaggatgt gaatgacaat gccccgcggt tcttccccag ccactgtgct gtggctgtct tcgacaacac cacagtgaag acccctgtgg ctgtagtatt tgcccgggat cccgaccaag gcgccaatgc ccaggtggtt tactctctgc cggattcagc cgaaggccac ttttccatcg acgccaccac gggggtgatc cgcctggaaa agccgctgca ggtcaggccc caggcaccac tggagctcac ggtccgtgcc tctgacctgg gcaccccaat accgctgtcc acgctgggca ccgtcacagt ctcggtggtg ggcctagaag actacctgcc cgtgttcctg aacaccgagc acagcgtgca ggtgcccgag gacgccccac ctggcacgga ggtgctgcag ctggccaccc tcactcgccc gggcgcagag aagaccggct accgcgtggt cagcgggaac gagcaaggca ggttccgcct ggatgctcgc acagggatcc tgtatgtcaa cgcaagcctg gactttgaga caagccccaa gtacttcctg tccattgagt gcagccggaa gagctcctct tccctcagtg acgtgaccac agtcatggtc aacatcactg atgtcaatga acaccggccc caattccccc aagatccata tagcacaagg gtcttagaga atgcccttgt gggtgacgtc atcctcacgg tatcagcgac tgatgaagat ggacccctaa atagtgacat tacctatagc ctcataggag ggaaccagct tgggcacttc accattcacc ccaaaaaggg ggagctacag gtggccaagg ccctggaccg ggaacaggcc tctagttatt ccctgaagct ccgagccaca gacagtgggc agcctccact gcatgaggac acagacatcg ctatccaagt ggctgatgtc aatgataacc caccgagatt cttccagctc aactacagca ccactgtcca ggagaactcc cccattggca gcaaagtcct gcagctgatc ctgagtgacc cagattctcc agagaatggc cccccctact cgtttcgaat caccaagggg aacaacggct ctgccttccg agtgaccccg gatggatggc tggtgactgc tgagggccta agcaggaggg ctcaggaatg gtatcagctt cagatccagg cgtcagacag tggcatccct cccctctcgt ctttgacgtc tgtccgtgtc catgtcacag agcagagcca ctatgcacct tctgctctcc cactggagat cttcatcact gttggagagg atgagttcca gggtggcatg gtgggtaaga tccatgccac agaccgagac ccccaggaca cgctgaccta tagcctggca gaagaggaga ccctgggcag gcacttctca gtgggtgcgc ctgatggcaa gattatcgcc gcccagggcc tgcctcgtgg ccactactcg ttcaacgtca cggtcagcga tgggaccttc accacgactg ctggggtcca tgtgtacgtg tggcatgtgg ggcaggaggc tctgcagcag gccatgtgga tgggcttcta ccagctcacc cccgaggagc tggtgagtga ccactggcgg aacctgcaga ggttcctcag ccataagctg gacatcaaac gggctaacat tcacttggcc agcctccagc ctgcagaggc cgtggctggt gtggatgtgc tcctggtctt tgaggggcat tctggaacct tctacgagtt tcaggagcta gcatccatca tcactcactc agccaaggag atggagcatt cagtgggggt tcagatgcgg tcagctatgc ccatggtgcc ctgccagggg ccaacctgcc agggtcaaat ctgccataac acagtgcatc tggaccccaa ggttgggccc acgtacagca ccgccaggct cagcatccta accccgcggc accacctgca gaggagctgc tcctgcaatg gtactgctac aaggttcagt ggtcagagct atgtgcggta cagggcccca gcggctcgga actggcacat ccatttctat ctgaaaacac tccagccaca ggccattctt ctattcacca atgaaacagc gtccgtctcc ctgaagctgg ccagtggagt gccccagctg gaataccact gtctgggtgg tttctatgga aacctttcct cccagcgcca tgtgaatgac cacgagtggc actccatcct ggtggaggag atggacgctt ccattcgcct gatggttgac agcatgggca acacctccct tgtggtccca gagaactgcc gtggtctgag gcccgaaagg cacctcttgc tgggcggcct cattctgttg cattcttcct cgaatgtctc ccagggcttt gaaggctgcc tggatgctgt cgtggtcaac gaagaggctc tagatctgct ggcccctggc aagacggtgg caggcttgct ggagacacaa gccctcaccc agtgctgcct ccacagtgac tactgcagcc agaacacatg cctcaatggt gggaagtgct catggaccca tggggcaggc tatgtctgca aatgtccccc acagttctct gggaagcact gtgaacaagg aagggagaac tgtacttttg caccctgcct ggaaggtgga acttgcatcc tctcccccaa aggagcttcc tgtaactgcc ctcatcctta cacaggagac aggtgtgaaa tggaggcgag gggttgttca gaaggacact gcctagtcac tcccgagatc caaagggggg actgggggca gcaggagtta ctgatcatca cagtggccgt ggcgttcatt atcataagca ctgtcgggct tctcttctac tgccgccgtt gcaagtctca caagcctgtg gccatggagg acccagacct cctggccagg agtgttggtg ttgacaccca agccatgcct gccatcgagc tcaacccatt gagtgccagc tcctgcaaca acctcaacca accggaaccc agcaaggcct ctgttccaaa tgaactcgtc acatttggac ccaattctaa gcaacggcca gtggtctgca gtgtgccccc cagactcccg ccagctgcgg tcccttccca ctctgacaat gagcctgtca ttaagagaac ctggtccagc gaggagatgg tgtaccctgg cggagccatg gtctggcccc ctacttactc caggaacgaa cgctgggaat acccccactc cgaagtgact cagggccctc tgccgccctc ggctcaccgc cactcaaccc cagtcgtgat gccagagcct aatggcctct atgggggctt ccccttcccc ctggagatgg aaaacaagcg ggcacctctc ccaccccgtt acagcaacca gaacctggaa gatctgatgc cctctcggcc ccctagtccc cgggagcgcc tggttgcccc ctgtctcaat gagtacacgg ccatcagcta ctaccactcg cagttccggc agggaggggg agggccctgc ctggcagacg ggggctacaa gggggtgggt atgcgcctca gccgagctgg gccctcttat gctgtctgtg aggtggaggg ggcacctctt gcaggccagg gccagccccg ggtgcccccc aactatgagg gctctgacat ggtggagagt gattatggca gctgtgagga ggtcatgttc tagcttccca ttcccagagc aaggcaggcg ggaggccaag gactggactt ggcttatttc ttcctgtctc gtagggggtg agttgagtgt ggctgggaga gtgggaggga agccctcagc ccaggctgtt gtcccttgaa atgtgctctt ccaatccccc acctagtccc tgagggtgga gggaagctga ggatagagct ccagaaacag cactagggtc ccaggagagg ggcatttcta gagcagtgac cctggaaaac caggaacaat tgactcctgg ggtgggcgac agacaggagg gctccctgat ctgccggctc tcagtccccg gggcaaagcc tgattgactg tgctggctca acttcaccaa gatgcattct catacctgcc cacagctcca ttttggaggc aggcaggttg gtgcctgaca gacaaccact acgcgggccg tacagaggag ctctagaggg ctgcgtggca tcctcctagg ggctgagagg tgagcagcag gggagcgggc acagtcccct ctgcccctgc ctcagtcgag cactcactgt gtctttgtca agtgtctgct ccacgtcagg cactgtgctt tgcaccgggg agaaaatggt gatggagggc aacaaggact ccgaggagca ccaccaggcc tcgggcccca gaggtcccgc tcctcagcct acacgcagag gaacgggccc acctcagagt cacaccactg gctgccagtc agggcctgcc aggagtctac acagctctga accttctttg ttaaagaatt cagacctcat ggaactctgg gttcttcatc ccaagtttcc caggcacttt tggccaaagg aaggaaggaa ctaattcttc attttaaaaa ttcttaggca ctttttgacc ttgctgtctg gatgagtttc ctcaatggga tttttcttcc ctagacacaa ggaagtctga actcctattt agggccggtt ggaagcaggg agctggaccg cagtgtccag gctggacacc tgccattgcc tcctctccac tgcagacgcc tgcccatcaa gtattacctg cagcgactca accctatgca tggagggtca atgtgggcac atgtctacac atgtgggtgc ccatggatag tacgtgtgta cacatgtgta gagtgtatgt agccaggagt ggtggggacc agaagcctct gtggcctttg gtgacctcac cactccctcc cacccagtcc ctccctctgg tccactgcct tttcatatgt gttgtttctg gagacagaag tcaaaaggaa gagcagtgga gccttgccca cagggctgct gcttcatgcg agagggagat gtgtgggcga gagccaattt gtgtgagtgg tttgtggctg tgtgtgtgac tgtgagtgtg agtgacagat acatagtttc attggtcatt ttttttttta acaataaagt atcttttttt actgtt SEQ ID NO: 24 Homo sapiens FAT tumor suppressor homolog 2 (Drosophila) (FAT2) (NP_001438.1) MTIALLGFAIFLLHCATCEKPLEGILSSSAWHFTHSHYNATIYENSSPKTYVESFEKMGIYLAEPQWAVRYRIIS GDVANVFKTEEYVVGNFCFLRIRTKSSNTALLNREVRDSYTLIIQATEKTLELEALTRVVVHILDQNDLKPLFSP PSYRVTISEDMPLKSPICKVTATDADLGQNAEFYYAFNTRSEMFAIHPTSGVVTVAGKLNVTWRGKHELQVLAVD RMRKISEGNGFGSLAALVVHVEPALRKPPAIASVVVTPPDSNDGTTYATVLVDANSSGAEVESVEVVGGDPGKHF KAIKSYARSNEFSLVSVKDINWMEYLHGFNLSLQARSGSGPYFYSQIRGFHLPPSKLSSLKFEKAVYRVQLSEFS PPGSRVVMVRVTPAFPNLQYVLKPSSENVGFKLNARTGLITTTKLMDFHDRAHYQLHIRTSPGQASTVVVIDIVD CNNHAPLFNRSSYDGTLDENIPPGTSVLAVTATDRDHGENGYVTYSIAGPKALPFSIDPYLGIISTSKPMEYELM KRIYTFRVRASDWGSPFRREKEVSIFLQLRNLNDNQPMFEEVNCTGSIRQDWPVGKSIMTMSAIDVDELQNLKYE IVSGNELEYFDLNHFSGVISLKRPFINLTAGQPTSYSLKITASDGKNYASPTTLNITVVKDPHFEVPVTCDKTGV LTQFTKTILHFIGLQNQESSDEEFTSLSTYQINHYTPQFEDHFPQSIDVLESVPINTPLARLAATDPDAGFNGKL VYVIADGNEEGCFDIELETGLLTVAAPLDYEATNFYILNVTVYDLGTPQKSSWKLLTVNVKDWNDNAPRFPPGGY QLTISEDTEVGTTIAELTTKDADSEDNGRVRYTLLSPTEKFSLHPLTGELVVTGHLDRESEPRYILKVEARDQPS KGHQLFSVTDLIITLEDVNDNSPQCITEHNRLKVPEDLPPGTVLTFLDASDPDLGPAGEVRYVLMDGAHGTFRVD LMTGALILERELDFERRAGYNLSLWASDGGRPLARRTLCHVEVIVLDVNENLHPPHFASFVEQGQVQENSPSGTQ VIVVAAQDDDSGLDGELQYFLRAGTGLAAFSINQDTGMIQTLAPLDREFASYYWLTVLAVDRGSVPLSSVTEVYI EVTDANDNPPQMSQAVFYPSIQEDAPVGTSVLQLDAWDPDSSSKGKLTFNITSGNYMGFFMIHPVTGLLSTAQQL DRENKDEHILEVTVLDNGEPSLKSTSRVVVGILDVNDNPPIFSHKLFNVRLPERLSPVSPGPVYRLVASDLDEGL NGRVTYSIEDSDEEAFSIDLVTGVVSSSSTFTAGEYNILTIKATDSGQPPLSASVRLHIEWIPWPRPSSIPLAFD ETYYSFTVMETDPVNHMVGVISVEGRPGLFWFNISGGDKDMDFDIEKTTGSIVIARPLDTRRRSNYNLTVEVTDG SRTIATQVHIFMIANINHHRPQFLETRYEVRVPQDTVPGVELLRVQAIDQDKGKSLIYTIHGSQDPGSASLFQLD PSSGVLVTVGKLDLGSGPSQHTLTVMVRDQEIPIKRNFVWVTIHVEDGNLHPPRFTQLHYEASVPDTIAPGTELL QVRAMDADRGVNAEVHYSLLKGNSEGFFNINALLGIITLAQKLDQANHAPHTLTVKAEDQGSPQWHDLATVIIHV YPSDRSAPIFSKSEYFVEIPESIPVGSPILLVSAMSPSEVTYELREGNKDGVFSMNSYSGLISTQKKLDHEKISS YQLKIRGSNMAGAFTDVMVVVDIIDENDNAPMFLKSTFVGQISEAAPLYSMIMDKNNNPFVIHASDSDKEANSLL VYKILEPEALKFFKIDPSMGTLTIVSEMDYESMPSFQFCVYVHDQGSPVLFAPRPAQVIIHVRDVNDSPPRFSEQ IYEVAIVGPIHPGMELLMVRASDEDSEVNYSIKTGNADEAVTIHPVTGSISVLNPAFLGLSRKLTIRASDGLYQD TALVKISLTQVLDKSLQFDQDVYWAAVKENLQDRKALVILGAQGNHLNDTLSYFLLNGTDMFHMVQSAGVLQTRG VAFDREQQDTHELAVEVRDNRTPQRVAQGLVRVSIEDVNDNPPKFKHLPYYTIIQDGTEPGDVLFQVSATDEDLG TNGAVTYEFAEDYTYFRIDPYLGDISLKKPFDYQALNKYHLKVIARDGGTPSLQSEEEVLVTVRNKSNPLFQSPY YKVRVPENITLYTPILHTQARSPEGLRLIYNIVEEEPLMLFTTDFKTGVLTVTGPLDYESKTKHVFTVRATDTAL GSFSEATVEVLVEDVNDNPPTFSQLVYTTSISEGLPAQTPVIQLLASDQDSGRNRDVSYQIVEDGSDVSKFFQIN GSTGEMSTVQELDYEAQQHFHVKVRAMDKGDPPLTGETLVVVNVSDINDNPPEFRQPQYEANVSELATCGHLVLK VQAIDPDSRDTSRLEYLILSGNQDRHFFINSSSGIISMFNLCKKHLDSSYNLRVGASDGVFRATVPVYINTTNAN KYSPEFQQHLYEAELAENAMVGTKVIDLLAIDKDSGPYGTIDYTIINKLASEKFSINPNGQIATLQKLDRENSTE RVIAIKVMARDGGGRVAFCTVKIILTDENDNPPQFKASEYTVSIQSNVSKDSPVIQVLAYDADEGQNADVTYSVN PEDLVKDVIEINPVTGVVKVKDSLVGLENQTLDFFIKAQDGGPPHWNSLVPVRLQVVPKKVSLPKFSEPLYTFSA PEDLPEGSEIGIVKAVAAQDPVIYSLVRGTTPESNKDGVFSLDPDTGVIKVRKPMDHESTKLYQIDVMAHCLQNT DVVSLVSVNIQVGDVNDNRPVFEADPYKAVLTENMPVGTSVIQVTAIDKDTGRDGQVSYRLSADPGSNVHELFAI DSESGWITTLQELDCETCQTYHFHVVAYDHGQTIQLSSQALVQVSITDENDNAPRFASEEYRGSVVENSEPGELV ATLKTLDADISEQNRQVTCYITEGDPLGQFGISQVGDEWRISSRKTLDREHTAKYLLRVTASDGKFQASVTVEIF VLDVNDNSPQCSQLLYTGKVHEDVFPGHFILKVSATDLDTDTNAQITYSLHGPGAHEFKLDPHTGELTTLTALDR ERKDVFNLVAKATDGGGRSCQADITLHVEDVNDNAPRFFPSHCAVAVFDNTTVKTPVAVVFARDPDQGANAQVVY SLPDSAEGHFSIDATTGVIRLEKPLQVRPQAPLELTVRASDLGTPIPLSTLGTVTVSVVGLEDYLPVFLNTEHSV QVPEDAPPGTEVLQLATLTRPGAEKTGYRVVSGNEQGRFRLDARTGILYVNASLDFETSPKYFLSIECSRKSSSS LSDVTTVMVNITDVNEHRPQFPQDPYSTRVLENALVGDVILTVSATDEDGPLNSDITYSLIGGNQLGHFTIHPKK GELQVAKALDREQASSYSLKLRATDSGQPPLHEDTDIAIQVADVNDNPPRFFQLNYSTTVQENSPIGSKVLQLIL SDPDSPENGPPYSFRITKGNNGSAFRVTPDGWLVTAEGLSRRAQEWYQLQIQASDSGIPPLSSLTSVRVHVTEQS HYAPSALPLEIFITVGEDEFQGGMVGKIHATDRDPQDTLTYSLAEEETLGRHFSVGAPDGKIIAAQGLPRGHYSF NVTVSDGTFTTTAGVHVYVWHVGQEALQQAMWMGFYQLTPEELVSDHWRNLQRFLSHKLDIKRANIHLASLQPAE AVAGVDVLLVFEGHSGTFYEFQELASIITHSAKEMEHSVGVQMRSAMPMVPCQGPTCQGQICHNTVHLDPKVGPT YSTARLSILTPRHHLQRSCSCNGTATRFSGQSYVRYRAPAARNWHIHFYLKTLQPQAILLFTNETASVSLKLASG VPQLEYHCLGGFYGNLSSQRHVNDHEWHSILVEEMDASIRLMVDSMGNTSLVVPENCRGLRPERHLLLGGLILLH SSSNVSQGFEGCLDAVVVNEEALDLLAPGKTVAGLLETQALTQCCLHSDYCSQNTCLNGGKCSWTHGAGYVCKCP PQFSGKHCEQGRENCTFAPCLEGGTCILSPKGASCNCPHPYTGDRCEMEARGCSEGHCLVTPEIQRGDWGQQELL IITVAVAFIIISTVGLLFYCRRCKSHKPVAMEDPDLLARSVGVDTQAMPAIELNPLSASSCNNLNQPEPSKASVP NELVTFGPNSKQRPVVCSVPPRLPPAAVPSHSDNEPVIKRTWSSEEMVYPGGAMVWPPTYSRNERWEYPHSEVTQ GPLPPSAHRHSTPVVMPEPNGLYGGFPFPLEMENKRAPLPPRYSNQNLEDLMPSRPPSPRERLVAPCLNEYTAIS YYHSQFRQGGGGPCLADGGYKGVGMRLSRAGPSYAVCEVEGAPLAGQGQPRVPPNYEGSDMVESDYGSCEEVMF SEQ ID NO: 25 Homo sapiens chemokine (C—X—C motif) ligand 5 (CECL5)(NM_002994) gtgcagaagg cacgaggaag ccacagtgct ccggatcctc caatcttcgc tcctccaatc tccgctcctc cacccagttc aggaacccgc gaccgctcgc agcgctctct tgaccactat gagcctcctg tccagccgcg cggcccgtgt ccccggtcct tcgagctcct tgtgcgcgct gttggtgctg ctgctgctgc tgacgcagcc agggcccatc gccagcgctg gtcctgccgc tgctgtgttg agagagctgc gttgcgtttg tttacagacc acgcaaggag ttcatcccaa aatgatcagt aatctgcaag tgttcgccat aggcccacag tgctccaagg tggaagtggt agcctccctg aagaacggga aggaaatttg tcttgatcca gaagcccctt ttctaaagaa agtcatccag aaaattttgg acggtggaaa caaggaaaac tgattaagag aaatgagcac gcatggaaaa gtttcccagt cttcagcaga gaagttttct ggaggtctct gaacccaggg aagacaagaa ggaaagattt tgttgttgtt tgtttatttg tttttccagt agttagcttt cttcctggat tcctcacttt gaagagtgtg aggaaaacct atgtttgccg cttaagcttt cagctcagct aatgaagtgt ttagcatagt acctctgcta tttgctgtta ttttatctgc tatgctattg aagttttggc aattgactat agtgtgagcc aggaatcact ggctgttaat ctttcaaagt gtcttgaatt gtaggtgact attatatttc caagaaatat tccttaagat attaactgag aaggctgtgg atttaatgtg gaaatgatgt ttcataagaa ttctgttgat ggaaatacac tgttatcttc acttttataa gaaataggaa atattttaat gtttcttggg gaatatgtta gagaatttcc ttactcttga ttgtgggata ctatttaatt atttcacttt agaaagctga gtgtttcaca ccttatctat gtagaatata tttccttatt cagaatttct aaaagtttaa gttctatgag ggctaatatc ttatcttcct ataattttag acattcttta tctttttagt atggcaaact gccatcattt acttttaaac tttgatttta tatgctattt attaagtatt ttattaggag taccataatt ctggtagcta aatatatatt ttagatagat gaagaagcta gaaaacaggc aaattcctga ctgctagttt atatagaaat gtattctttt agtttttaaa gtaaaggcaa acttaacaat gacttgtact ctgaaagttt tggaaacgta ttcaaacaat ttgaatataa atttatcatt tagttataaa aatatatagc gacatcctcg aggccctagc atttctcctt ggatagggga ccagagagag cttggaatgt taaaaacaaa acaaaacaaa aaaaaacaag gagaagttgt ccaagggatg tcaatttttt atccctctgt atgggttaga ttttccaaaa tcataatttg aagaaggcca gcatttatgg tagaatatat aattatatat aaggtggcca cgctggggca agttccctcc ccactcacag ctttggcccc tttcacagag tagaacctgg gttagaggat tgcagaagac gagcggcagc ggggagggca gggaagatgc ctgtcgggtt tttagcacag ttcatttcac tgggattttg aagcatttct gtctgaatgt aaagcctgtt ctagtcctgg tgggacacac tggggttggg ggtgggggaa gatgcggtaa tgaaaccggt tagtcagtgt tgtcttaata tccttgataa tgctgtaaag tttattttta caaatatttc tgtttaagct atttcacctt tgtttggaaa tccttccctt ttaaagagaa aatgtgacac ttgtgaaaag gcttgtagga aagctcctcc ctttttttct ttaaaccttt aaatgacaaa cctaggtaat taatggttgt gaatttctat ttttgctttg tttttaatga acatttgtct ttcagaatag gattctgtga taatatttaa atggcaaaaa caaaacataa ttttgtgcaa ttaacaaagc tactgcaaga aaaataaaac atttcttggt aaaaacgtat gtatttatat attatatatt tatatataat atatattata tatttagcat tgctgagctt tttagatgcc tattgtgtat cttttaaagg ttttgaccat tttgttatga gtaattacat atatattaca ttcactatat taaaattgta cttttttact atgtgtctca ttggttcata gtctttattt tgtcctttga ataaacatta aaagatttct aaacttcaaa aaaaaaaaaa aaaaa SEQ ID NO: 26 Homo sapiens chemokine (C—X—C motif) ligand 5 (CXCL5) (NP_002985.1) MSLLSSRAARVPGPSSSLCALLVLLLLLTQPGPIASAGPAAAVLRELRCVCLQTTQGVHPKMISNLQVFAIGPQC SKVEVVASLKNGKEICLDPEAPFLKKVIQKILDGGNKEN SEQ ID NO: 27 Homo sapiens zinc finger protein 771 (ZNF771) (NM_016643) gaggtggtga aactcaagat ccccatggac aacaaggagg tcccgggcga ggcgcccgcg ccgtccgccg acccggcgcg tccccacgcg tgccccgact gcggccgcgc cttcgcgcgc cgctccacgc tggcgaagca cgcgcgcacg cacacgggcg aacggccctt cgggtgcacc gagtgcgggc ggcgcttctc acagaagtcg gcgctgacca aacacggccg cacgcacacg ggcgagcggc cctacgagtg ccccgagtgc gacaaacgct tctcggccgc ctcgaacctg cggcagcacc gacggcggca cacgggcgag aagccgtacg catgcgcgca ctgcggccgc cgcttcgcgc agagctccaa ctacgcacag cacctgcgcg tgcacacggg cgagaagccg tacgcgtgcc cggactgcgg acgcgccttt ggcggcagct cgtgcctggc gcgccaccga cgcacgcaca cgggcgagcg gccctacgct tgcgccgact gcggcacgcg cttcgctcag agctcggcgc tggccaagca ccggcgcgtg cacacgggcg agaagccgca ccgctgcgct gtgtgtggcc gtcgcttcgg ccaccgctcc aacctggcgg agcacgcgcg cacgcacaca ggcgagcggc cctacccctg cgccgagtgc ggccgccgct tccgcctaag ctcgcacttc attcgccacc gacgcgcgca catgcggcgc cgcctgtata tttgcgccgg ctgcggcagg gacttcaagc tgccccctgg cgccacggcc gccactgcca ccgagcgttg cccggagtgt gagggcagct gagtcccgca gggctgcgga ggggcgcgct ggggcttcga cctggctgca ctaacccagg ctcctcctcg ccccggcctc cgggtctggg aaattgaggg gacggcaggc ccggctgccc tggaactggg agacagggag aatcccctgc cggggtccct ggaaacagtg cccaccccac atcactacat tccctcggcc cgtgttagtg aataaagtat tatatcctca ccccacccgt gcctgtgagt gaggtgggtg ggagaggaag aaagttgggg ttctccaggc tcaggtgcca agtgagttgt caaggaacca aatggggatg taaacctaaa aggggttccc ggcacctcgg tttgtgttgg ttggaggtga tcgcacactt ggcccttggt tacgtcctca taaccttaga cctgaaaggg cccataaata tactatgttc acgatcagac acgcactgca ttcggcagag ctccagtgag caaggcacga ccctcagatc tcagtctagt gaaggagaga aaactgtaat aacactacgt taaaggtttt aactgctttg ttatgtaagc ttacccagcc cggcgcacag tgactcacgc ctgtaatccc agcactttgg gagggcgagg ctagcagatc acttgaggtt aggagttcga taccagcctg gccaacatgg tgaaacccgg tctctactaa aaatacaaaa attaactggg tgtggtggcg ggcgcctgta atcccagcta ctgagggggc tgaggcatga gaatcacttg aacctgggag acagaggttg caatgaaccg agatagtgcc attgcactcc ggcctgggca acagaggaag actgcctcaa acaaacaaaa aacaacaaac caaaccaaac caaaaaaatc tcaaagcgat tggacctagc agctcatgcc tgtaatctcc agcactttgg gaggcggagg caggaggatc tcttgaagtc aagagtttga gatcagcctg gagaacaaag tgagaccccc atctattaaa aaaaaaaaaa aaaaa SEQ ID NO: 28 Homo sapiens zinc finger protein 771 (ZNF771)(NP_057727.1) MDNKEVPGEAPAPSADPARPHACPDCGRAFARRSTLAKHARTHTGERPFGCTECGRRFSQKSALTKHGRTHTGER PYECPECDKRFSAASNLRQHRRRHTGEKPYACAHCGRRFAQSSNYAQHLRVHTGEKPYACPDCGRAFGGSSCLAR HRRTHTGERPYACADCGTRFAQSSALAKHRRVHTGEKPHRCAVCGRRFGHRSNLAEHARTHTGERPYPCAECGRR FRLSSHFIRHRRAHMRRRLYICAGCGRDFKLPPGATAATATERCPECEGS SEQ ID NO: 29 Homo sapiens natriuretic peptide receptor C/guanylate cyclase C (atrionatriuretic peptide receptor C)(NPR3)(NM_000908) tctttttctt ttttttttaa gaaaaactag tgacattgca gagaaggacg cttcctctct atcttttggc gcattagtga agggggtatt ctattttgtt aaagcgccca agggggcgca gggaccttgg agagaagagt ggggaggaaa gaggaagggt gggtgggggg cagagggcga gtcggcggcg gcgagggcaa gctctttctt gcggcacgat gccgtctctg ctggtgctca ctttctcccc gtgcgtacta ctcggctggg cgttgctggc cggcggcacc ggtggcggtg gcgttggcgg cggcggcggt ggcgcgggca taggcggcgg acgccaggag agagaggcgc tgccgccaca gaagatcgag gtgctggtgt tactgcccca ggatgactcg tacttgtttt cactcacccg ggtgcggccg gccatcgagt atgctctgcg cagcgtggag ggcaacggga ctgggaggcg gcttctgccg ccgggcactc gcttccaggt ggcttacgag gattcagact gtgggaaccg tgcgctcttc agcttggtgg accgcgtggc ggcggcgcgg ggcgccaagc cagaccttat cctggggcca gtgtgcgagt atgcagcagc gccagtggcc cggcttgcat cgcactggga cctgcccatg ctgtcggctg gggcgctggc cgctggcttc cagcacaagg actctgagta ctcgcacctc acgcgcgtgg cgcccgccta cgccaagatg ggcgagatga tgctcgccct gttccgccac caccactgga gccgcgctgc actggtctac agcgacgaca agctggagcg gaactgctac ttcaccctcg agggggtcca cgaggtcttc caggaggagg gtttgcacac gtccatctac agtttcgacg agaccaaaga cttggatctg gaagacatcg tgcgcaatat ccaggccagt gagagagtgg tgatcatgtg tgcgagcagt gacaccatcc ggagcatcat gctggtggcg cacaggcatg gcatgaccag tggagactac gccttcttca acattgagct cttcaacagc tcttcctatg gagatggctc atggaagaga ggagacaaac acgactttga agctaagcaa gcatactcgt ccctccagac agtcactcta ctgaggacag tgaaacctga gtttgagaag ttttccatgg aggtgaaaag ttcagttgag aaacaagggc tcaatatgga ggattacgtt aacatgtttg ttgaaggatt ccacgatgcc atcctcctct acgtcttggc tctacatgaa gtactcagag ctggttacag caaaaaggat ggagggaaaa ttatacagca gacttggaac agaacatttg aaggtatcgc cgggcaggtg tccatagatg ccaacggaga ccgatatggg gatttctctg tgattgccat gactgatgtg gaggcgggca cccaggaggt tattggtgat tattttggaa aagaaggtcg ttttgaaatg cggccgaatg tcaaatatcc ttggggccct ttaaaactga gaatagatga aaaccgaatt gtagagcata caaacagctc tccctgcaaa tcatgtggcc tagaagaatc ggcagtgaca ggaattgtcg tgggggcttt actaggagct ggcttgctaa tggccttcta ctttttcagg aagaaataca gaataaccat tgagaggcga acccagcaag aagaaagtaa ccttggaaaa catcgggaat tacgggaaga ttccatcaga tcccattttt cagtagctta aaggaagccc cccacttttt ttttttctgc ctgagattct ttaaggagat agacgggttg aaagacatca atgaaacaga aggggcgttc ttgaagaatt cataatttta agcagttagt aatttcattt taaaatttct gtagaagctc aggaattatg attaatcacc atctgcctcc aggcctttca tctcatgaca aacaaatata ataatgatat cgtgtcactc tgttaaatgt tcatactgtt tcaagcccat atgattagat ttatgttttt aaaatctgtt gtctccatat cttgatggct tttgggagca tttcacacaa ggatataaaa tgcggttttc ttaaatgaaa tgttttgtag ctagaataaa atcattttta caagtacagc attcttggaa agaatttaac acccaaaaag gggaaaatgt aatgaaaaat ctcaaggttg gaaatacagc cttactctct ctagagctgg aggacaggtt tgtggttgag gacttctctg tccgatgtct acattcaggt tctgacttca tatcttgaaa aaggatttcc tccctgtctt tttcagtgtc tcataaacgc tactctggat tgttgtaaat attagtgaga tgggaggatt tacagaagaa aagcaagtca aaaatatttc ctttttgatg taaaaaaaaa aagccctatt tcgcactaac attttatttt acaagtattt taatcttata ttttggtatt agaaaaattt gtctattttt tcattttgaa gattaaatgt tgcttacatt ttaaaaaaaa a SEQ ID NO: 30 Homo sapiens natriuretic peptide receptor C/guanylate cyclase C (atrionatriuretic peptide receptor C) (NPR3) (NP_000899.1) MPSLLVLTFSPCVLLGWALLAGGTGGGGVGGGGGGAGIGGGRQEREALPPQKIEVLVLLPQDDSYLFSLTRVRPA IEYALRSVEGNGTGRRLLPPGTRFQVAYEDSDCGNRALFSLVDRVAAARGAKPDLILGPVCEYAAAPVARLASHW DLPMLSAGALAAGFQHKDSEYSHLTRVAPAYAKMGEMMLALFRHHHWSRAALVYSDDKLERNCYFTLEGVHEVFQ EEGLHTSIYSFDETKDLDLEDIVRNIQASERVVIMCASSDTIRSIMLVAHRHGMTSGDYAFFNIELFNSSSYGDG SWKRGDKHDFEAKQAYSSLQTVTLLRTVKPEFEKFSMEVKSSVEKQGLNMEDYVNMFVEGFHDAILLYVLALHEV LRAGYSKKDGGKIIQQTWNRTFEGIAGQVSIDANGDRYGDFSVIAMTDVEAGTQEVIGDYFGKEGRFEMRPNVKY PWGPLKLRIDENRIVEHTNSSPCKSCGLEESAVTGIVVGALLGAGLLMAFYFFRKKYRITIERRTQQEESNLGKH RELREDSIRSHFSVA SEQ ID NO: 31 Homo sapiens early growth response 2 (Krox-20 homolog, Drosophila) (EGR2) (NM_000399) taactgagcg aggagcaatt gattaatagc tcggcgaggg gactcactga ctgttataat aacactacac cagcaactcc tggcttccca gcagccggaa cacagacagg agagagtcag tggcaaatag acatttttct tatttcttaa aaaacagcaa cttgtttgct acttttattt ctgttgattt ttttttcttg gtgtgtgtgg tacttgtttt taagtgtgga gggcaaaagg agataccatc ccaggctcag tccaacccct ctccaaaacg gcttttctga cactccaggt agcgagggag ttgggtctcc aggttgtgcg aggagcaaat gatgaccgcc aaggccgtag acaaaatccc agtaactctc agtggttttg tgcaccagct gtctgacaac atctacccgg tggaggacct cgccgccacg tcggtgacca tctttcccaa tgccgaactg ggaggcccct ttgaccagat gaacggagtg gccggagatg gcatgatcaa cattgacatg actggagaga agaggtcgtt ggatctccca tatcccagca gctttgctcc cgtctctgca cctagaaacc agaccttcac ttacatgggc aagttctcca ttgaccctca gtaccctggt gccagctgct acccagaagg cataatcaat attgtgagtg caggcatctt gcaaggggtc acttccccag cttcaaccac agcctcatcc agcgtcacct ctgcctcccc caacccactg gccacaggac ccctgggtgt gtgcaccatg tcccagaccc agcctgacct ggaccacctg tactctccgc caccgcctcc tcctccttat tctggctgtg caggagacct ctaccaggac ccttctgcgt tcctgtcagc agccaccacc tccacctctt cctctctggc ctacccacca cctccttcct atccatcccc caagccagcc acggacccag gtctcttccc aatgatccca gactatcctg gattctttcc atctcagtgc cagagagacc tacatggtac agctggccca gaccgtaagc cctttccctg cccactggac accctgcggg tgccccctcc actcactcca ctctctacaa tccgtaactt taccctgggg ggccccagtg ctggggtgac cggaccaggg gccagtggag gcagcgaggg accccggctg cctggtagca gctcagcagc agcagcagcc gccgccgccg ccgcctataa cccacaccac ctgccactgc ggcccattct gaggcctcgc aagtacccca acagacccag caagacgccg gtgcacgaga ggccctaccc gtgcccagca gaaggctgcg accggcggtt ctcccgctct gacgagctga cacggcacat ccgaatccac actgggcata agcccttcca gtgtcggatc tgcatgcgca acttcagccg cagtgaccac ctcaccaccc atatccgcac ccacaccggt gagaagccct tcgcctgtga ctactgtggc cgaaagtttg cccggagtga tgagaggaag cgccacacca agatccacct gagacagaaa gagcggaaaa gcagtgcccc ctctgcatcg gtgccagccc cctctacagc ctcctgctct gggggcgtgc agcctggggg taccctgtgc agcagtaaca gcagcagtct tggcggaggg ccgctcgccc cttgctcctc tcggacccgg acaccttgag atgagactca ggctgataca ccagctccca aaggtcccgg aggccctttg tccactggag ctgcacaaca aacactacca ccctttcctg tccctctctc cctttgttgg gcaaagggct ttggtggagc tagcactgcc ccctttccac ctagaagcag gttcttccta aaacttagcc cattctagtc tctcttaggt gagttgacta tcaacccaag gcaaagggga ggctcagaag gaggtggtgt ggggatcccc tggccaagag ggctgaggtc tgaccctgct ttaaagggtt gtttgactag gttttgctac cccacttccc cttattttga cccatcacag gtttttgacc ctggatgtca gagttgatct aagacgtttt ctacaatagg ttgggagatg ctgatccctt caagtgggga cagcaaaaag acaagcaaaa ctgatgtgca ctttatggct tgggactgat ttgggggaca ttgtacagtg agtgaagtat agcctttatg ccacactctg tggccctaaa atggtgaatc agagcatatc tagttgtctc aacccttgaa gcaatatgta ttatatactc agagaacaga agtgcaatgt gatgggagga acgtagcaat atctgctcct tttcgagttg tttgagaaat gtaggctatt ttttcagtgt atatccactc agattttgtg tatttttgat gtacccacac tgttctctaa attctgaatc tttgggaaaa aatgtaaagc atttatgatc tcagaggtta acttatttaa gggggatgta catattctct gaaactagga tgcatgcaat tgtgttggaa gtgtccttgg tcgccttgtg tgatgtagac aaatgttaca aggctgcatg taaatgggtt gccttattat ggagaaaaaa atcactccct gagtttagta tggctgtata tttatgccta ttaatatttg gaattttttt tagaaagtat atttttgtat gctttgtttt gtgacttaaa agtgttacct ttgtagtcaa atttcagata agaatgtaca taatgttacc ggagctgatt tgtttggtca ttagctctta atagttgtga aaaaataaat ctattctaac gcaaaaccac taactgaagt tcagatataa tggatggttt gtgactatag tgtaaataaa tacttttcaa caat SEQ ID NO: 32 Homo sapiens early growth response 2 (Krox-20 homolog, Drosophila) (EGR2) (NP_000390.2) MMTAKAVDKIPVTLSGFVHQLSDNIYPVEDLAATSVTIFPNAELGGPFDQMNGVAGDGMINIDMTGEKRSLDLPY PSSFAPVSAPRNQTFTYMGKFSIDPQYPGASCYPEGIINIVSAGILQGVTSPASTTASSSVTSASPNPLATGPLG VCTMSQTQPDLDHLYSPPPPPPPYSGCAGDLYQDPSAFLSAATTSTSSSLAYPPPPSYPSPKPATDPGLFPMIPD YPGFFPSQCQRDLHGTAGPDRKPFPCPLDTLRVPPPLTPLSTIRNFTLGGPSAGVTGPGASGGSEGPRLPGSSSA AAAAAAAAAYNPHHLPLRPILRPRKYPNRPSKTPVHERPYPCPAEGCDRRFSRSDELTRHIRIHTGHKPFQCRIC MRNFSRSDHLTTHIRTHTGEKPFACDYCGRKFARSDERKRHTKIHLRQKERKSSAPSASVPAPSTASCSGGVQPG GTLCSSNSSSLGGGPLAPCSSRTRTP SEQ ID NO: 33 Homo sapiens leukocyte immunoglobulin-like receptor, subfamily A (with TM domain), member 4 (LILRA4) (NM_012276) ctacgggcac cgtggccaca cctgcctgca cagccagggc caggaggagg agatgccatg accctcattc tcacaagcct gctcttcttt gggctgagcc tgggccccag gacccgggtg caggcagaaa acctacccaa acccatcctg tgggccgagc caggtcccgt gatcacctgg cataaccccg tgaccatctg gtgtcagggc accctggagg cccaggggta ccgtctggat aaagagggaa actcaatgtc gaggcacata ttaaaaacac tggagtctga aaacaaggtc aaactctcca tcccatccat gatgtgggaa catgcagggc gatatcactg ttactatcag agccctgcag gctggtcaga gcccagcgac cccctggagc tggtggtgac agcctacagc agacccaccc tgtccgcact gccaagccct gtggtgacct caggagtgaa cgtgaccctc cggtgtgcct cacggctggg actgggcagg ttcactctga ttgaggaagg agaccacagg ctctcctgga ccctgaactc acaccaacac aaccatggaa agttccaggc cctgttcccc atgggccccc tgaccttcag caacaggggt acattcagat gctacggcta tgaaaacaac accccatacg tgtggtcgga acccagtgac cccctgcagc tactggtgtc aggcgtgtct aggaagccct ccctcctgac cctgcagggc cctgtcgtga cccccggaga gaatctgacc ctccagtgtg gctctgatgt cggctacatc agatacactc tgtacaagga gggggccgat ggcctccccc agcgccctgg ccggcagccc caggctgggc tctcccaggc caacttcacc ctgagccctg tgagccgctc ctacgggggc cagtacagat gctacggcgc acacaacgtc tcctccgagt ggtcggcccc cagtgacccc ctggacatcc tgatcgcagg acagatctct gacagaccct ccctctcagt gcagccgggc cccacggtga cctcaggaga gaaggtgacc ctgctgtgtc agtcatggga cccgatgttc actttccttc tgaccaagga gggggcagcc catcccccgt tgcgtctgag atcaatgtac ggagctcata agtaccaggc tgaattcccc atgagtcctg tgacctcagc ccacgcgggg acctacaggt gctacggctc acgcagctcc aacccctacc tgctgtctca ccccagtgag cccctggagc tcgtggtctc aggagcaact gagaccctca atccagcaca aaagaagtca gattccaaga ctgccccaca cctccaggat tacacagtgg agaatctcat ccgcatgggt gtggctggct tggtcctgct gttcctcggg attctgttat ttgaggctca gcacagccag agaagccccc caaggtgcag ccaggaggca aacagcagaa aggacaatgc acccttcaga gtggtggagc cttgggaaca gatctgatga tctgaggagg ttctggaaga ctggggcagc agttggggaa gtgtctgctg agaatatcaa ggggaagaag catgggtcag gtgcaggaag atgtctgggt gtctgtagaa gatgcttcct ccattaaact gtggtgcttt cctcctcaaa aaaaaaaaaa aaaaa SEQ ID NO: 34 Homo sapiens leukocyte immunoglobulin-like receptor, subfamily A (with TM domain), member 4 (LILRA4) (NP_036408.3) MTLILTSLLFFGLSLGPRTRVQAENLPKPILWAEPGPVITWHNPVTIWCQGTLEAQGYRLDKEGNSMSRHILKTL ESENKVKLSIPSMMWEHAGRYHCYYQSPAGWSEPSDPLELVVTAYSRPTLSALPSPVVTSGVNVTLRCASRLGLG RFTLIEEGDHRLSWTLNSHQHNHGKFQALFPMGPLTFSNRGTFRCYGYENNTPYVWSEPSDPLQLLVSGVSRKPS LLTLQGPVVTPGENLTLQCGSDVGYIRYTLYKEGADGLPQRPGRQPQAGLSQANFTLSPVSRSYGGQYRCYGAHN VSSEWSAPSDPLDILIAGQISDRPSLSVQPGPTVTSGEKVTLLCQSWDPMFTFLLTKEGAAHPPLRLRSMYGAHK YQAEFPMSPVTSAHAGTYRCYGSRSSNPYLLSHPSEPLELVVSGATETLNPAQKKSDSKTAPHLQDYTVENLIRM GVAGLVLLFLGILLFEAQHSQRSPPRCSQEANSRKDNAPFRVVEPWEQI SEQ ID NO: 35 Homo sapiens prostaglandin D2 synthase 21 kDa (brain) (PTGDS) (NM_000954) gctcctcctg cacacctccc tcgctctccc acaccactgg caccaggccc cggacacccg ctctgctgca ggagaatggc tactcatcac acgctgtgga tgggactggc cctgctgggg gtgctgggcg acctgcaggc agcaccggag gcccaggtct ccgtgcagcc caacttccag caggacaagt tcctggggcg ctggttcagc gcgggcctcg cctccaactc gagctggctc cgggagaaga aggcggcgtt gtccatgtgc aagtctgtgg tggcccctgc cacggatggt ggcctcaacc tgacctccac cttcctcagg aaaaaccagt gtgagacccg aaccatgctg ctgcagcccg cggggtccct cggctcctac agctaccgga gtccccactg gggcagcacc tactccgtgt cagtggtgga gaccgactac gaccagtacg cgctgctgta cagccagggc agcaagggcc ctggcgagga cttccgcatg gccaccctct acagccgaac ccagaccccc agggctgagt taaaggagaa attcaccgcc ttctgcaagg cccagggctt cacagaggat accattgtct tcctgcccca aaccgataag tgcatgacgg aacaatagga ctccccaggg ctgaagctgg gatcccggcc agccaggtga cccccacgct ctggatgtct ctgctctgtt ccttccccga gcccctgccc cggctccccg ccaaagcaac cctgcccact caggcttcat cctgcacaat aaactccgga agcaagtcag taaaaaaaaa aaaaaaaaaa aaaaaaa SEQ ID NO: 36 Homo sapiens prostaglandin D2 synthase 21 kDa (brain) (PTGDS) (NP_000945.3) MATHHTLWMGLALLGVLGDLQAAPEAQVSVQPNFQQDKFLGRWFSAGLASNSSWLREKKAALSMCKSVVAPATDG GLNLTSTFLRKNQCETRTMLLQPAGSLGSYSYRSPHWGSTYSVSVVETDYDQYALLYSQGSKGPGEDFRMATLYS RTQTPRAELKEKFTAFCKAQGFTEDTIVFLPQTDKCMTEQ SEQ ID NO: 37 Homo sapiens periostin, osteoblast specific factor (POSTN) (NM_006475) agagactcaa gatgattccc tttttaccca tgttttctct actattgctg cttattgtta accctataaa cgccaacaat cattatgaca agatcttggc tcatagtcgt atcaggggtc gggaccaagg cccaaatgtc tgtgcccttc aacagatttt gggcaccaaa aagaaatact tcagcacttg taagaactgg tataaaaagt ccatctgtgg acagaaaacg actgttttat atgaatgttg ccctggttat atgagaatgg aaggaatgaa aggctgccca gcagttttgc ccattgacca tgtttatggc actctgggca tcgtgggagc caccacaacg cagcgctatt ctgacgcctc aaaactgagg gaggagatcg agggaaaggg atccttcact tactttgcac cgagtaatga ggcttgggac aacttggatt ctgatatccg tagaggtttg gagagcaacg tgaatgttga attactgaat gctttacata gtcacatgat taataagaga atgttgacca aggacttaaa aaatggcatg attattcctt caatgtataa caatttgggg cttttcatta accattatcc taatggggtt gtcactgtta attgtgctcg aatcatccat gggaaccaga ttgcaacaaa tggtgttgtc catgtcattg accgtgtgct tacacaaatt ggtacctcaa ttcaagactt cattgaagca gaagatgacc tttcatcttt tagagcagct gccatcacat cggacatatt ggaggccctt ggaagagacg gtcacttcac actctttgct cccaccaatg aggcttttga gaaacttcca cgaggtgtcc tagaaaggtt catgggagac aaagtggctt ccgaagctct tatgaagtac cacatcttaa atactctcca gtgttctgag tctattatgg gaggagcagt ctttgagacg ctggaaggaa atacaattga gataggatgt gacggtgaca gtataacagt aaatggaatc aaaatggtga acaaaaagga tattgtgaca aataatggtg tgatccattt gattgatcag gtcctaattc ctgattctgc caaacaagtt attgagctgg ctggaaaaca gcaaaccacc ttcacggatc ttgtggccca attaggcttg gcatctgctc tgaggccaga tggagaatac actttgctgg cacctgtgaa taatgcattt tctgatgata ctctcagcat ggttcagcgc ctccttaaat taattctgca gaatcacata ttgaaagtaa aagttggcct taatgagctt tacaacgggc aaatactgga aaccatcgga ggcaaacagc tcagagtctt cgtatatcgt acagctgtct gcattgaaaa ttcatgcatg gagaaaggga gtaagcaagg gagaaacggt gcgattcaca tattccgcga gatcatcaag ccagcagaga aatccctcca tgaaaagtta aaacaagata agcgctttag caccttcctc agcctacttg aagctgcaga cttgaaagag ctcctgacac aacctggaga ctggacatta tttgtgccaa ccaatgatgc ttttaaggga atgactagtg aagaaaaaga aattctgata cgggacaaaa atgctcttca aaacatcatt ctttatcacc tgacaccagg agttttcatt ggaaaaggat ttgaacctgg tgttactaac attttaaaga ccacacaagg aagcaaaatc tttctgaaag aagtaaatga tacacttctg gtgaatgaat tgaaatcaaa agaatctgac atcatgacaa caaatggtgt aattcatgtt gtagataaac tcctctatcc agcagacaca cctgttggaa atgatcaact gctggaaata cttaataaat taatcaaata catccaaatt aagtttgttc gtggtagcac cttcaaagaa atccccgtga ctgtctatac aactaaaatt ataaccaaag ttgtggaacc aaaaattaaa gtgattgaag gcagtcttca gcctattatc aaaactgaag gacccacact aacaaaagtc aaaattgaag gtgaacctga attcagactg attaaagaag gtgaaacaat aactgaagtg atccatggag agccaattat taaaaaatac accaaaatca ttgatggagt gcctgtggaa ataactgaaa aagagacacg agaagaacga atcattacag gtcctgaaat aaaatacact aggatttcta ctggaggtgg agaaacagaa gaaactctga agaaattgtt acaagaagag gtcaccaagg tcaccaaatt cattgaaggt ggtgatggtc atttatttga agatgaagaa attaaaagac tgcttcaggg agacacaccc gtgaggaagt tgcaagccaa caaaaaagtt caaggttcta gaagacgatt aagggaaggt cgttctcagt gaaaatccaa aaaccagaaa aaaatgttta tacaacccta agtcaataac ctgaccttag aaaattgtga gagccaagtt gacttcagga actgaaacat cagcacaaag aagcaatcat caaataattc tgaacacaaa tttaatattt ttttttctga atgagaaaca tgagggaaat tgtggagtta gcctcctgtg gtaaaggaat tgaagaaaat ataacacctt acaccctttt tcatcttgac attaaaagtt ctggctaact ttggaatcca ttagagaaaa atccttgtca ccagattcat tacaattcaa atcgaagagt tgtgaactgt tatcccattg aaaagaccga gccttgtatg tatgttatgg atacataaaa tgcacgcaag ccattatctc tccatgggaa gctaagttat aaaaataggt gcttggtgta caaaactttt tatatcaaaa ggctttgcac atttctatat gagtgggttt actggtaaat tatgttattt tttacaacta attttgtact ctcagaatgt ttgtcatatg cttcttgcaa tgcatatttt ttaatctcaa acgtttcaat aaaaccattt ttcagatata aagagaatta cttcaaattg agtaattcag aaaaactcaa gatttaagtt aaaaagtggt ttggacttgg gaa SEQ ID NO: 38 Homo sapiens periostin, osteoblast specific factor (POSTN) (NP_006466.1) MIPFLPMFSLLLLLIVNPINANNHYDKILAHSRIRGRDQGPNVCALQQILGTKKKYFSTCKNWYKKSICGQKTTV LYECCPGYMRMEGMKGCPAVLPIDHVYGTLGIVGATTTQRYSDASKLREEIEGKGSFTYFAPSNEAWDNLDSDIR RGLESNVNVELLNALHSHMINKRMLTKDLKNGMIIPSMYNNLGLFINHYPNGVVTVNCARIIHGNQIATNGVVHV IDRVLTQIGTSIQDFIEAEDDLSSFRAAAITSDILEALGRDGHFTLFAPTNEAFEKLPRGVLERFMGDKVASEAL MKYHILNTLQCSESIMGGAVFETLEGNTIEIGCDGDSITVNGIKMVNKKDIVTNNGVIHLIDQVLIPDSAKQVIE LAGKQQTTFTDLVAQLGLASALRPDGEYTLLAPVNNAFSDDTLSMVQRLLKLILQNHILKVKVGLNELYNGQILE TIGGKQLRVFVYRTAVCIENSCMEKGSKQGRNGAIHIFREIIKPAEKSLHEKLKQDKRFSTFLSLLEAADLKELL TQPGDWTLFVPTNDAFKGMTSEEKEILIRDKNALQNIILYHLTPGVFIGKGFEPGVTNILKTTQGSKIFLKEVND TLLVNELKSKESDIMTTNGVIHVVDKLLYPADTPVGNDQLLEILNKLIKYIQIKFVRGSTFKEIPVTVYTTKIIT KVVEPKIKVIEGSLQPIIKTEGPTLTKVKIEGEPEFRLIKEGETITEVIHGEPIIKKYTKIIDGVPVEITEKETR EERIITGPEIKYTRISTGGGETEETLKKLLQEEVTKVTKFIEGGDGHLFEDEEIKRLLQGDTPVRKLQANKKVQG SRRRLREGRSQ SEQ ID NO: 39 Homo sapiens wingless-type MMTV integration site family, member 5A (WNT5A) (NM_003392) agttgcctgc gcgccctcgc cggaccggcg gctccctagt tgcgccccga ccaggccctg cccttgctgc cggctcgcgc gcgtccgcgc cccctccatt cctgggcgca tcccagctct gccccaactc gggagtccag gcccgggcgc cagtgcccgc ttcagctccg gttcactgcg cccgccggac gcgcgccgga ggactccgca gccctgctcc tgaccgtccc cccaggctta acccggtcgc tccgctcgga ttcctcggct gcgctcgctc gggtggcgac ttcctccccg cgccccctcc ccctcgccat gaagaagtcc attggaatat taagcccagg agttgctttg gggatggctg gaagtgcaat gtcttccaag ttcttcctag tggctttggc catatttttc tccttcgccc aggttgtaat tgaagccaat tcttggtggt cgctaggtat gaataaccct gttcagatgt cagaagtata tattatagga gcacagcctc tctgcagcca actggcagga ctttctcaag gacagaagaa actgtgccac ttgtatcagg accacatgca gtacatcgga gaaggcgcga agacaggcat caaagaatgc cagtatcaat tccgacatcg aaggtggaac tgcagcactg tggataacac ctctgttttt ggcagggtga tgcagatagg cagccgcgag acggccttca catacgcggt gagcgcagca ggggtggtga acgccatgag ccgggcgtgc cgcgagggcg agctgtccac ctgcggctgc agccgcgccg cgcgccccaa ggacctgccg cgggactggc tctggggcgg ctgcggcgac aacatcgact atggctaccg ctttgccaag gagttcgtgg acgcccgcga gcgggagcgc atccacgcca agggctccta cgagagtgct cgcatcctca tgaacctgca caacaacgag gccggccgca ggacggtgta caacctggct gatgtggcct gcaagtgcca tggggtgtcc ggctcatgta gcctgaagac atgctggctg cagctggcag acttccgcaa ggtgggtgat gccctgaagg agaagtacga cagcgcggcg gccatgcggc tcaacagccg gggcaagttg gtacaggtca acagccgctt caactcgccc accacacaag acctggtcta catcgacccc agccctgact actgcgtgcg caatgagagc accggctcgc tgggcacgca gggccgcctg tgcaacaaga cgtcggaggg catggatggc tgcgagctca tgtgctgcgg ccgtggctac gaccagttca agaccgtgca gacggagcgc tgccactgca agttccactg gtgctgctac gtcaagtgca agaagtgcac ggagatcgtg gaccagtttg tgtgcaagta gtgggtgcca cccagcactc agccccgctc ccaggacccg cttatttata gaaagtacag tgattctggt ttttggtttt tagaaatatt ttttattttt ccccaagaat tgcaaccgga accatttttt ttcctgttac catctaagaa ctctgtggtt tattattaat attataatta ttatttggca ataatggggg tgggaaccaa gaaaaatatt tattttgtgg atctttgaaa aggtaataca agacttcttt tgatagtata gaatgaaggg gaaataacac ataccctaac ttagctgtgt ggacatggta cacatccaga aggtaaagaa atacattttc tttttctcaa atatgccatc atatgggatg ggtaggttcc agttgaaaga gggtggtaga aatctattca caattcagct tctatgacca aaatgagttg taaattctct ggtgcaagat aaaaggtctt gggaaaacaa aacaaaacaa aacaaacctc ccttccccag cagggctgct agcttgcttt ctgcattttc aaaatgataa tttacaatgg aaggacaaga atgtcatatt ctcaaggaaa aaaggtatat cacatgtctc attctcctca aatattccat ttgcagacag accgtcatat tctaatagct catgaaattt gggcagcagg gaggaaagtc cccagaaatt aaaaaattta aaactcttat gtcaagatgt tgatttgaag ctgttataag aattaggatt ccagattgta aaaagatccc caaatgattc tggacactag atttttttgt ttggggaggt tggcttgaac ataaatgaaa atatcctgtt attttcttag ggatacttgg ttagtaaatt ataatagtaa aaataataca tgaatcccat tcacaggttc tcagcccaag caacaaggta attgcgtgcc attcagcact gcaccagagc agacaaccta tttgaggaaa aacagtgaaa tccaccttcc tcttcacact gagccctctc tgattcctcc gtgttgtgat gtgatgctgg ccacgtttcc aaacggcagc tccactgggt cccctttggt tgtaggacag gaaatgaaac attaggagct ctgcttggaa aacagttcac tacttaggga tttttgtttc ctaaaacttt tattttgagg agcagtagtt ttctatgttt taatgacaga acttggctaa tggaattcac agaggtgttg cagcgtatca ctgttatgat cctgtgttta gattatccac tcatgcttct cctattgtac tgcaggtgta ccttaaaact gttcccagtg tacttgaaca gttgcattta taagggggga aatgtggttt aatggtgcct gatatctcaa agtcttttgt acataacata tatatatata tacatatata taaatataaa tataaatata tctcattgca gccagtgatt tagatttaca gtttactctg gggttatttc tctgtctaga gcattgttgt ccttcactgc agtccagttg ggattattcc aaaagttttt tgagtcttga gcttgggctg tggccctgct gtgatcatac cttgagcacg acgaagcaac cttgtttctg aggaagcttg agttctgact cactgaaatg cgtgttgggt tgaagatatc ttttttcttt tctgcctcac ccctttgtct ccaacctcca tttctgttca ctttgtggag agggcattac ttgttcgtta tagacatgga cgttaagaga tattcaaaac tcagaagcat cagcaatgtt tctcttttct tagttcattc tgcagaatgg aaacccatgc ctattagaaa tgacagtact tattaattga gtccctaagg aatattcagc ccactacata gatagctttt tttttttttt ttttaataag gacacctctt tccaaacagt gccatcaaat atgttcttat ctcagactta cgttgtttta aaagtttgga aagatacaca tctttcatac cccccttagg caggttggct ttcatatcac ctcagccaac tgtggctctt aatttattgc ataatgatat tcacatcccc tcagttgcag tgaattgtga gcaaaagatc ttgaaagcaa aaagcactaa ttagtttaaa atgtcacttt tttggttttt attatacaaa aaccatgaag tacttttttt atttgctaaa tcagattgtt cctttttagt gactcatgtt tatgaagaga gttgagttta acaatcctag cttttaaaag aaactattta atgtaaaata ttctacatgt cattcagata ttatgtatat cttctagcct ttattctgta cttttaatgt acatatttct gtcttgcgtg atttgtatat ttcactggtt taaaaaacaa acatcgaaag gcttatgcca aatggaagat agaatataaa ataaaacgtt acttgtatat tggtaagtgg tttcaattgt ccttcagata attcatgtgg agatttttgg agaaaccatg acggatagtt taggatgact acatgtcaaa gtaataaaag agtggtgaat tttaccaaaa ccaagctatt tggaagcttc aaaaggtttc tatatgtaat ggaacaaaag gggaattctc ttttcctata tatgttcctt acaaaaaaaa aaaaaaaaga aatcaagcag atggcttaaa gctggttata ggattgctca cattctttta gcattatgca tgtaacttaa ttgttttaga gcgtgttgct gttgtaacat cccagagaag aatgaaaagg cacatgcttt tatccgtgac cagattttta gtccaaaaaa atgtattttt ttgtgtgttt accactgcaa ctattgcacc tctctatttg aatttactgt ggaccatgtg tggtgtctct atgccctttg aaagcagttt ttataaaaag aaagcccggg tctgcagaga atgaaaactg gttggaaact aaaggttcat tgtgttaagt gcaattaata caagttattg tgcttttcaa aaatgtacac ggaaatctgg acagtgctgc acagattgat acattagcct ttgctttttc tctttccgga taaccttgta acatattgaa accttttaag gatgccaaga atgcattatt ccacaaaaaa acagcagacc aacatataga gtgtttaaaa tagcatttct gggcaaattc aaactcttgt ggttctagga ctcacatctg tttcagtttt tcctcagttg tatattgacc agtgttcttt attgcaaaaa catatacccg atttagcagt gtcagcgtat tttttcttct catcctggag cgtattcaag atcttcccaa tacaagaaaa ttaataaaaa atttatatat aggcagcagc aaaagagcca tgttcaaaat agtcattatg ggctcaaata gaaagaagac ttttaagttt taatccagtt tatctgttga gttctgtgag ctactgacct cctgagactg gcactgtgta agttttagtt gcctacccta gctcttttct cgtacaattt tgccaatacc aagtttcaat ttgtttttac aaaacattat tcaagccact agaattatca aatatgacgc tatagcagag taaatactct gaataagaga ccggtactag ctaactccaa gagatcgtta gcagcatcag tccacaaaca cttagtggcc cacaatatat agagagatag aaaaggtagt tataacttga agcatgtatt taatgcaaat aggcacgaag gcacaggtct aaaatactac attgtcactg taagctatac ttttaaaata tttatttttt ttaaagtatt ttctagtctt ttctctctct gtggaatggt gaaagagaga tgccgtgttt tgaaagtaag atgatgaaat gaatttttaa ttcaagaaac attcagaaac ataggaatta aaacttagag aaatgatcta atttccctgt tcacacaaac tttacacttt aatctgatga ttggatattt tattttagtg aaacatcatc ttgttagcta actttaaaaa atggatgtag aatgattaaa ggttggtatg attttttttt aatgtatcag tttgaaccta gaatattgaa ttaaaatgct gtctcagtat tttaaaagca aaaaaggaat ggaggaaaat tgcatcttag accattttta tatgcagtgt acaatttgct gggctagaaa tgagataaag attatttatt tttgttcata tcttgtactt ttctattaaa atcattttat gaaatccaaa aaaaaaaaaa aaaaa SEQ ID NO: 40 Homo sapiens wingless-type MMTV integration site family, member 5A (WNT5A) (NP_003383.2) MKKSIGILSPGVALGMAGSAMSSKFFLVALAIFFSFAQVVIEANSWWSLGMNNPVQMSEVYIIGAQPLCSQLAGL SQGQKKLCHLYQDHMQYIGEGAKTGIKECQYQFRHRRWNCSTVDNTSVFGRVMQIGSRETAFTYAVSAAGVVNAM SRACREGELSTCGCSRAARPKDLPRDWLWGGCGDNIDYGYRFAKEFVDARERERIHAKGSYESARILMNLHNNEA GRRTVYNLADVACKCHGVSGSCSLKTCWLQLADFRKVGDALKEKYDSAAAMRLNSRGKLVQVNSRFNSPTTQDLV YIDPSPDYCVRNESTGSLGTQGRLCNKTSEGMDGCELMCCGRGYDQFKTVQTERCHCKFHWCCYVKCKKCTEIVD QFVCK SEQ ID NO: 41 Homo sapiens prostaglandin D2 synthase 21 kDa (brain) (PTGDS) (NM_000954) gctcctcctg cacacctccc tcgctctccc acaccactgg caccaggccc cggacacccg ctctgctgca ggagaatggc tactcatcac acgctgtgga tgggactggc cctgctgggg gtgctgggcg acctgcaggc agcaccggag gcccaggtct ccgtgcagcc caacttccag caggacaagt tcctggggcg ctggttcagc gcgggcctcg cctccaactc gagctggctc cgggagaaga aggcggcgtt gtccatgtgc aagtctgtgg tggcccctgc cacggatggt ggcctcaacc tgacctccac cttcctcagg aaaaaccagt gtgagacccg aaccatgctg ctgcagcccg cggggtccct cggctcctac agctaccgga gtccccactg gggcagcacc tactccgtgt cagtggtgga gaccgactac gaccagtacg cgctgctgta cagccagggc agcaagggcc ctggcgagga cttccgcatg gccaccctct acagccgaac ccagaccccc agggctgagt taaaggagaa attcaccgcc ttctgcaagg cccagggctt cacagaggat accattgtct tcctgcccca aaccgataag tgcatgacgg aacaatagga ctccccaggg ctgaagctgg gatcccggcc agccaggtga cccccacgct ctggatgtct ctgctctgtt ccttccccga gcccctgccc cggctccccg ccaaagcaac cctgcccact caggcttcat cctgcacaat aaactccgga agcaagtcag taaaaaaaaa aaaaaaaaaa aaaaaaa SEQ ID NO: 42 Homo sapiens prostaglandin D2 synthase 21 kDa (brain) (PTGDS) (NP_000945.3) MATHHTLWMGLALLGVLGDLQAAPEAQVSVQPNFQQDKFLGRWFSAGLASNSSWLREKKAALSMCKSVVAPATDG GLNLTSTFLRKNQCETRTMLLQPAGSLGSYSYRSPHWGSTYSVSVVETDYDQYALLYSQGSKGPGEDFRMATLYS RTQTPRAELKEKFTAFCKAQGFTEDTIVFLPQTDKCMTEQ SEQ ID NO: 43 Homo sapiens defensin, alpha 3, neutrophil-specific (DEFA3) (NM_005217) ccttgctata gaagacctgg gacagaggac tgctgtctgc cctctctggt caccctgcct agctagagga tctgtgaccc cagccatgag gaccctcgcc atccttgctg ccattctcct ggtggccctg caggcccagg ctgagccact ccaggcaaga gctgatgagg ttgctgcagc cccggagcag attgcagcgg acatcccaga agtggttgtt tcccttgcat gggacgaaag cttggctcca aagcatccag gctcaaggaa aaacatggac tgctattgca gaataccagc gtgcattgca ggagaacgtc gctatggaac ctgcatctac cagggaagac tctgggcatt ctgctgctga gcttgcagaa aaagaaaaat gagctcaaaa tttgctttga gagctacagg gaattgctat tactcctgta ccttctgctc aatttccttt cctcatctca aataaatgcc ttgttac SEQ ID NO: 44 Homo sapiens defensin, alpha 3, neutrophil-specific (DEFA3) (NP_005208.1) MRTLAILAAILLVALQAQAEPLQARADEVAAAPEQIAADIPEVVVSLAWDESLAPKHPGSRKNMDCYCRIPACIA GERRYGTCIYQGRLWA SEQ ID NO: 45 Homo sapiens POU domain, class 1, transcription factor 1 (Pit1, growth hormone factor 1) (POU1F1) (NM_000306) ctcagagcct tcctgatgta tatatgcagg tagtgagaat tgaatcggcc ctttgagaca gtaatataat aaaactctga tttggggagc agcggttctc cttatttttc tactctcttg tgggaatgag ttgccaagct tttacttcgg ctgatacctt tatacctctg aattctgacg cctctgcaac tctgcctctg ataatgcatc acagtgctgc cgagtgtcta ccagtctcca accatgccac caatgtgatg tctacagcaa caggacttca ttattctgtt ccttcctgtc attatggaaa ccagccatca acctatggag tgatggcagg tagtttaacc ccttgtcttt ataaatttcc tgaccacacc ttgagtcatg gatttcctcc tatacaccag cctcttctgg cagaggaccc cacagctgct gatttcaagc aggaactcag gcggaaaagt aaattggtgg aagagccaat agacatggat tctccagaaa tcagagaact tgaaaagttt gccaatgaat ttaaagtgag acgaattaaa ttaggataca cccagacaaa tgttggggag gccctggcag ctgtgcatgg ctctgaattc agtcaaacaa caatctgccg atttgaaaat ctgcagctca gctttaaaaa tgcatgcaaa ctgaaagcaa tattatccaa atggctggag gaagctgagc aagtaggagc tttgtacaat gaaaaagtgg gagcaaatga aaggaaaaga aaacgaagaa caactataag cattgctgct aaagatgctc tggagagaca ctttggagaa cagaataaac cttcttctca agagatcatg aggatggctg aagaactgaa tctggagaaa gaagtagtaa gagtttggtt ttgcaaccgg aggcagagag aaaaacgggt gaaaacaagt ctgaatcaga gtttattttc tatttctaag gaacatcttg agtgcagata agatttttct attgtataat agcctttttc tcccgtttca ttcctttctc ttcctcaaca aaaacagaaa ttacttggtt gacttaaaat cattttatat caatagcttt tacagaagct ttacttttcc actttttttt aaaaaaaaga aaccaacaat ttaaattata ttgatgttat ttacttaaaa taattattct cagaagccac attatctatt ttaagccaaa tatattaaca gtaataaaat gatctctctg tc SEQ ID NO: 46 Homo sapiens POU domain, class 1, transcription factor 1 (Pit1, growth hormone factor 1) (POU1F1) (NP_000297.1) MSCQAFTSADTFIPLNSDASATLPLIMHHSAAECLPVSNHATNVMSTATGLHYSVPSCHYGNQPSTYGVMAGSLT PCLYKFPDHTLSHGFPPIHQPLLAEDPTAADFKQELRRKSKLVEEPIDMDSPEIRELEKFANEFKVRRIKLGYTQ TNVGEALAAVHGSEFSQTTICRFENLQLSFKNACKLKAILSKWLEEAEQVGALYNEKVGANERKRKRRTTISIAA KDALERHFGEQNKPSSQEIMRMAEELNLEKEVVRVWFCNRRQREKRVKTSLNQSLFSISKEHLECR SEQ ID NO: 47 Homo sapiens cadherin 13, H-cadherin (heart) (CDH13) (NM_001257) gggaagttgg ctggctggcg aggcagagcc tctcctcaaa gcctggctcc cacggaaaat atgctcagtg cagccgcgtg catgaatgaa aacgccgccg ggcgcttcta gtcggacaaa atgcagccga gaactccgct cgttctgtgc gttctcctgt cccaggtgct gctgctaaca tctgcagaag atttggactg cactcctgga tttcagcaga aagtgttcca tatcaatcag ccagctgaat tcattgagga ccagtcaatt ctaaacttga ccttcagtga ctgtaaggga aacgacaagc tacgctatga ggtctcgagc ccatacttca aggtgaacag cgatggcggc ttagttgctc tgagaaacat aactgcagtg ggcaaaactc tgttcgtcca tgcacggacc ccccatgcgg aagatatggc agaactcgtg attgtcgggg ggaaagacat ccagggctcc ttgcaggata tatttaaatt tgcaagaact tctcctgtcc caagacaaaa gaggtccatt gtggtatctc ccattttaat tccagagaat cagagacagc ctttcccaag agatgttggc aaggtagtcg atagtgacag gccagaaagg tccaagttcc ggctcactgg aaagggagtg gatcaagagc ctaaaggaat tttcagaatc aatgagaaca cagggagcgt ctccgtgaca cggaccttgg acagagaagt aatcgctgtt tatcaactat ttgtggagac cactgatgtc aatggcaaaa ctctcgaggg gccggtgcct ctggaagtca ttgtgattga tcagaatgac aaccgaccga tctttcggga aggcccctac atcggccacg tcatggaagg gtcacccaca ggcaccacag tgatgcggat gacagccttt gatgcagatg acccagccac cgataatgcc ctcctgcggt ataatatccg tcagcagacg cctgacaagc catctcccaa catgttctac atcgatcctg agaaaggaga cattgtcact gttgtgtcac ctgcgctgct ggaccgagag actctggaaa atcccaagta tgaactgatc atcgaggctc aagatatggc tggactggat gttggattaa caggcacggc cacagccacg atcatgatcg atgacaaaaa tgatcactca ccaaaattca ccaagaaaga gtttcaagcc acagtcgagg aaggagctgt gggagttatt gtcaatttga cagttgaaga taaggatgac cccaccacag gtgcatggag ggctgcctac accatcatca acggaaaccc cgggcagagc tttgaaatcc acaccaaccc tcaaaccaac gaagggatgc tttctgttgt caaaccattg gactatgaaa tttctgcctt ccacaccctg ctgatcaaag tggaaaatga agacccactc gtacccgacg tctcctacgg ccccagctcc acagccaccg tccacatcac tgtcctggat gtcaacgagg gcccagtctt ctacccagac cccatgatgg tgaccaggca ggaggacctc tctgtgggca gcgtgctgct gacagtgaat gccacggacc ccgactccct gcagcatcaa accatcaggt attctgttta caaggaccca gcaggttggc tgaatattaa ccccatcaat gggactgttg acaccacagc tgtgctggac cgtgagtccc catttgtcga caacagcgtg tacactgctc tcttcctggc aattgacagt ggcaaccctc ccgctacggg cactgggact ttgctgataa ccctggagga cgtgaatgac aatgccccgt tcatttaccc cacagtagct gaagtctgtg atgatgccaa aaacctcagt gtagtcattt tgggagcatc agataaggat cttcacccga atacagatcc tttcaaattt gaaatccaca aacaagctgt tcctgataaa gtctggaaga tctccaagat caacaataca cacgccctgg taagccttct tcaaaatctg aacaaagcaa actacaacct gcccatcatg gtgacagatt cagggaaacc acccatgacg aatatcacag atctcagggt acaagtgtgc tcctgcagga attccaaagt ggactgcaac gcggcagggg ccctgcgctt cagcctgccc tcagtcctgc tcctcagcct cttcagctta gcttgtctgt gagaactcct gacgtctgaa gcttgactcc caagtttcca tagcaacagg aaaaaaaaaa atctatccaa atctgaagat tgcggtttac agctatcgaa cttcacaact aggcctcaat tgttccggtt ttttattttc tttacaattt cacttagtct gtacttcatc attttgacag catcttcctc cctcctttaa ttaatggaat cttctgaatt ttccctgaat gtttaaagat catgacatat gacttgatct tctgggagca ggaacaatga ctactttttc tggtgtgtta acatgtcgct agccagtgct ccaggcaccc agctttgtct gtgggttagt attggtgtat gtatgagtat ctgtatgtat atatacacgg tatttataga gagagactat cctggagaag cctcgttttg atgccattct tccttgcaag gttaagcaag gtgggtggaa actaagacac ctgaaccctc cagggcctcc cgcatcaagg tcagcatgag gacagaccac agagctgtca cttttgctcc gaagctactt ctccactgtc ccgttcagtc tgaatgctgc cacaaccagc caggcaggtc cacagagagg gagagcagag aaagaagtcc tttctcttta ttgagttcga ggactacaac caatttacac tgccatctga tgccgtgatc ctgagccaag gaggtgagga gcagagcagg caatttcacc accaaatgcc aagaaaaggg ctgacatttt ctttcatggg caccaacctg catttgtatg tgtcccgaat ccacagtcgt actgattcta atggggacac agatcatggt agagaatctc tccctcctca gtaaatgtac aactgcacct gtcatcatgg aggtcataca tgcatacaaa gaggtgtaca ggtaccatct tgtatacaca tatataccca catgtacaga catacattta tgcacattca cgctgtttgt ttcatatata caggcataaa atagagtaaa tacaggtagt tttaaaagta cccttttgtg tgaattgact accgttgttt gcaaacccga aaataaaaga cgttcattat gtatgaaaag taactgattt gtattctgtg agcatgtaaa agcggaaagt tagtgcttgt tctaagatta ccttcttgtt gataaaccat aaatgaatca tcaaagctca caccaaattt ttctatcaaa taaaactagt gacagcttgt ggctttttat tagagctcgc cacgaactag ggtaaggtga gtgtcttagc atattttaat gcagttgctt actaaaggtt ttaaccgcac atgcacacac acacgctttc ttatgcaatc tatgtttgca cttgtgcttt cagttagcct tctgtaggaa gtagaagtca tatgttgtct ttgttgtagt gaaattatac agatagagtt ccatatattg tatttgtttc aatggtaaat ccttttggaa catatagaat gcagagattt ttttttccat taaaataaat gggtattggt ggttaaaaaa aaaaaaaaaa aa SEQ ID NO: 48 Homo sapiens cadherin 13, H-cadherin (heart) (CDH13) (NP_001248.1) MQPRTPLVLCVLLSQVLLLTSAEDLDCTPGFQQKVFHINQPAEFIEDQSILNLTFSDCKGNDKLRYEVSSPYFKV NSDGGLVALRNITAVGKTLFVHARTPHAEDMAELVIVGGKDIQGSLQDIFKFARTSPVPRQKRSIVVSPILIPEN QRQPFPRDVGKVVDSDRPERSKFRLTGKGVDQEPKGIFRINENTGSVSVTRTLDREVIAVYQLFVETTDVNGKTL EGPVPLEVIVIDQNDNRPIFREGPYIGHVMEGSPTGTTVMRMTAFDADDPATDNALLRYNIRQQTPDKPSPNMFY IDPEKGDIVTVVSPALLDRETLENPKYELIIEAQDMAGLDVGLTGTATATIMIDDKNDHSPKFTKKEFQATVEEG AVGVIVNLTVEDKDDPTTGAWRAAYTIINGNPGQSFEIHTNPQTNEGMLSVVKPLDYEISAFHTLLIKVENEDPL VPDVSYGPSSTATVHITVLDVNEGPVFYPDPMMVTRQEDLSVGSVLLTVNATDPDSLQHQTIRYSVYKDPAGWLN INPINGTVDTTAVLDRESPFVDNSVYTALFLAIDSGNPPATGTGTLLITLEDVNDNAPFIYPTVAEVCDDAKNLS VVILGASDKDLHPNTDPFKFEIHKQAVPDKVWKISKINNTHALVSLLQNLNKANYNLPIMVTDSGKPPMTNITDL RVQVCSCRNSKVDCNAAGALRFSLPSVLLLSLFSLACL SEQ ID NO: 49 Homo sapiens tripartite motif-containing 58 (TRIM58) (NM_015431) gggagacggt gcgggcggcc gggagcgcag ccctccggga ggcgggtcat ggcctgggcg ccgcccgggg agcggctgcg cgaggatgcg cggtgcccgg tgtgcctgga tttcctgcag gagccggtca gcgtggactg cggccacagc ttctgcctca ggtgcatctc cgagttctgc gagaagtcgg acggcgcgca gggcggcgtc tacgcctgtc cgcagtgccg gggccccttc cggccctcgg gctttcgccc caaccggcag ctggcgggcc tggtggagag cgtgcggcgg ctggggttgg gcgcggggcc cggggcgcgg cgatgcgcgc ggcacggcga ggacctgagc cgcttctgcg aggaggacga ggcggcgctg tgctgggtgt gcgacgccgg ccccgagcac aggacgcacc gcacggcgcc gctgcaggag gccgccggca gctaccaggt aaagctccag atggctctgg aacttatgag gaaagagttg gaggacgcct tgactcagga ggccaacgtg gggaaaaaga ctgtcatttg gaaggagaaa gtggaaatgc agaggcagcg cttcagattg gagtttgaga agcatcgtgg ctttctggcc caggaggagc aacggcagct gaggcggctg gaggcggagg agcgagcgac gctgcagaga ctgcgggaga gcaagagccg gctggtccag cagagcaagg ccctgaagga gctggcggat gagctgcagg agaggtgcca gcgcccggcc ctgggtctgc tggagggtgt gagaggagtc ctgagcagaa gtaaggctgt cacaaggctg gaagcagaga acatccccat ggaactgaag acagcatgct gcatccctgg gaggagggag ctcttaagga agttccaagt ggatgtaaag ctggatcccg ccacggcgca cccgagtctg ctcttgaccg ccgacctgcg cagtgtgcag gatggagaac catggaggga tgtccccaac aaccctgagc gatttgacac atggccctgc atcctgggtt tgcagagctt ctcatcaggg aggcattact gggaggttct ggtgggagaa ggagcagagt ggggtttagg ggtctgtcaa gacacactgc caagaaaggg ggaaaccacg ccatctcctg agaatggggt ctgggccctg tggctgctga aagggaatga gtacatggtc cttgcctccc catcagtgcc tcttctccaa ctggaaagtc ctcgctgcat tgggattttc ttggactatg aagccggtga aatttcattc tacaatgtca cagatggatc ttatatctac acattcaacc aactcttctc tggtcttctt cggccttact ttttcatctg tgatgcaact cctcttatct tgccacccac aacaatagca gggtcaggaa attgggcatc cagggatcat ttagatcctg cttctgatgt aagagatgat catctctaaa attctgttcc caagatgcag tcctagcgta gcgaacgttc ctggagtggg gtgaaggata tcaatatact aagttttaac agatacccca tttaggtcag cacttgattc gttgttgctg tgaaatatgt ccatgggaca aaagagggaa tatgaaatat ttgcatatgg gaagattata gagcataata attttgtaaa tggagcaatc tcaacctcta tttctagatc acattttctt gatgtcttcc ttcaaattaa tgaccttgga ttacataagg atttctatgc attcattata atttgttatt cctttcaata tccttgtatt tcaaatcttc catataagaa ttagacatgg caattcttaa attgattcag aatggtctga tactattcca gtatcacctc cttaattctg tttctcctcg ttttcctgat tttccttctc attctctcct tccccgctct gtctctctct ccctgtcact ctctctctct tgttccttat tttttgtttc ttacctctta ctgtttaacc tgttgcttcc ttctggatta atacatttag agccattcct ttatatggtc acatttccta tgactttact caattacttt taaaatcctt tctattctga gactaatttt taagaattac aaagctcatt cttctgaatc taatatcact aactcctaga ctttttccgt tttctttgga tacactttaa gtaggaattt atcagaattt tcattcaact cgttctttaa tgcagatatt tactagttat aagaccttaa ggctgggtgc agtggctcac gcctgtaatc ccagcacttt gggaggctga ggcgggtgga tcacaagctc aggagttcaa gaccagcctg gccaacatgg tgaaaccctg tctctactaa aaaaaaaaaa aaaatagaaa aattagctgg gcatggtggc aggagcctgt aatcccagct attctggagg tggagacagg agaattgctt gaaccctgga ggcggaggtt gcagtgagcc aatatctcac cactgtactc cagcccagtg cgagactcca tctcaaaaaa gaaaaaagac ctcaaacaac acttctctct ctcttttagc tgcttgttat ggttcctata catggaacaa ttatactggc ctcactgtgt tatggtaaat atttaaggtc atatttgata ttgctggttt gaattcagct tttccattta aatacattat aatgatgatg atgaaatcat gataatattt aacttatttt taaagtatat tctgtacctt tccaacaaaa aggttaaaag tcattgaagg ctaaccttac tgccttcttt gtatcactgt cttctaaata attattatgt ctgggtacag tggctcacgc ctgtaatccc agcactttgg gaggccgagg tgggcagatc acgaggtcag gagattgaga ccatcctggc taacacagtg aaaccccgtc tctactaaaa atacaaaaag aaattagctg ggcgtggtgg tgggtgcctg ttgtcccagc tacttgggag gctgaggcag gagaatggca tgaacccagg aggcagagct tgtagtgagc cgagatcgcg ccactgcact ccagccgggg caacagagca agactccatc tcaaaaataa ataaataaat aaataaataa ataaataaat aaataaatat tacacaaatg ctaaaatgtt taaatggtaa atgcttcaat gctaaccaaa tattaattaa tggcaaatta tttaacatta tctgataata atctgcagaa ggtttaattt tcctcctcaa tttgaagttc aagatgtttt tctcttccag ggagattttt tcgactgaca tctttaactt accttccaat catattacta acgtagcctt cttcctagat tttttaattg tttgatcatg agcgaacact tctactctct gtgatagatt tgcaaacaga ggaaataacg catcctcgtg tccctcttct tggtgttcca caggccatgt gtgccctagc cctcgttcat gcaaggtctg tgtagggaag gtggacttca gctcagcaac agcatccctt cccacaggga tcaggtgggt ggcttgagat accccttcca tggggcacca cccattcagt gagacgggga agccctgggt gggagggaga acacctccac atgtcttcta ctctctccat aggatggaat gagtgtccca gtcccaggag tatccatttc ccactgtgta gcccagtact ctggtctcac tgtctctgct gaatcctgtc tcactgtgca tattattgtg gtttatatca gtcagtaaac caatgtgagt cttcatctct tgcattctta ggttcatagt tttgtgtgtc tcctgtaatg actcttctct ttccctttcc aactcctgaa agattgccac tatttcctct ggaactttgt ttcgttacca gcaaaatcct cgacatccat acccgtttcc tggctttccc tctcctttcc tctgaatggt agtcttttat attcagctgt ccacttgaca tcaaaataga cattttgaac tcaatttgcc taaaacttac ccacaaattt ctccccaagt ctctccctaa ctgcaacaac aaaaaccaca ggcttctccc tgtcactgga tggcaactcc attcttttga ttgcttaagc caggcatccg attgagtact ttcttgattt ctccagccca catccagtcc atcggcaagc cctgttggtc ctaccttcag aatatgtccg gggttcagtt gtcctggcca ccctgctgct gtaaccatgg tcagaactcc atcctgcccc tctggattat gactttcgtt tcctcacagt ggtcctgctt gggctctagg cccttccact cccattctct ctacagcagc tgggctgatt cctttagcac ccaaggatat gttggcatca cagtgactta gataccatca caaagacctc ccattcaact tagagtgaaa gtcagaatcc tcacagtgaa tccccaggcc ctagaggatg tgaaccccca ggccctagag gatctgaacc cccatccctc ctctgattat ctctcccacc cccacttccc tttgcattct gctccagctg ccctggcctc atggctgggt ttccaccaaa gcaggcactt cccatcacag ggccatttcc ccgcctgtgg cttctgcttg acattccctt ttccctgata tccccttgac tcattattcc ctttcttcct taactcttct gagatccagc ttctcagtga taccacacag ccctactccc cccagagccc atctagagct cacctttcca gtcgcccttg ccaggctcag tggaggctct ttgttcccca tacagtacgt gtcgtcgtac tatattgtta ggcttattta atttatgtat gttttgcctt tttgtgctaa atgtaaacac cacaagggga ggtatctttg tctgttgaca atgatacatt caatgtttct caagcacccc caatgctggt ttgtatgtgg 5101 ttatcattca atctgtattt gttgaatgaa taaatgattg actatgtgga gagcaaaa SEQ ID NO: 58 Homo sapiens tripartite motif-containing 58 (TRIM58) (NP_056246.3) MAWAPPGERLREDARCPVCLDFLQEPVSVDCGHSFCLRCISEFCEKSDGAQGGVYACPQCRGPFRPSGFRPNRQL AGLVESVRRLGLGAGPGARRCARHGEDLSRFCEEDEAALCWVCDAGPEHRTHRTAPLQEAAGSYQVKLQMALELM RKELEDALTQEANVGKKTVIWKEKVEMQRQRFRLEFEKHRGFLAQEEQRQLRRLEAEERATLQRLRESKSRLVQQ SKALKELADELQERCQRPALGLLEGVRGVLSRSKAVTRLEAENIPMELKTACCIPGRRELLRKFQVDVKLDPATA HPSLLLTADLRSVQDGEPWRDVPNNPERFDTWPCILGLQSFSSGRHYWEVLVGEGAEWGLGVCQDTLPRKGETTP SPENGVWALWLLKGNEYMVLASPSVPLLQLESPRCIGIFLDYEAGEISFYNVTDGSYIYTFNQLFSGLLRPYFFI CDATPLILPPTTIAGSGNWASRDHLDPASDVRDDHL SEQ ID NO: 59 Homo sapiens Zwilch, kinetochore associated, homolog (Drosophila) (ZWILCH) (NM_017975) agtcgaggta tcttctcccc aaccactgct cttattttaa ttattgcaga cggaagttga agactattga catagtaaat agctctgggt ggcttgaaac gaaagtttaa ctttgcggac aaacaggact tattgtaggg ggtggtcaaa atagtcccgg cggggcgggg ccatgacccc tgacgtcgcc ggtccggcgc gcagttcagt ttggcggttc cggtaccgct ctcacattgg ggcgggatgt gggagcggct gaactgcgca gcagaggact tttattctcg tctccttcag aaatttaatg aagaaaagaa aggaatccgt aaagacccat ttctctatga ggctgatgtc caagtgcagt tgatcagcaa aggccaacca aaccctttga aaaatattct aaatgaaaat gacatagtat tcatagtgga aaaagtgcct ttagaaaagg aagaaacaag tcatattgaa gaacttcaat ctgaagaaac tgccatatct gatttctcta ctggcgaaaa tgttggacca cttgctttac cagttgggaa ggcaaggcag ttaattggac tttacaccat ggctcacaat cctaatatga cccatttgaa gattaatctg ccagttactg cccttcctcc cctttgggta agatgtgaca gttcagatcc tgaaggtact tgttggctag gagctgagct tatcacaaca aacaacagca ttacaggaat tgtcttatat gtggtcagtt gtaaagctga taaaaattat tctgtaaatc ttgaaaacct aaaaaattta cacaagaaaa gacatcactt gtctactgta acatccaaag gctttgccca gtatgagctc tttaagtcct ctgccttgga tgatacaatc acagcatcac aaactgcgat cgctttggat atttcctgga gtcctgtgga tgagattctt caaatccctc cactctcttc aactgcaact ctgaatatta aagtggaatc aggagagccc agaggtcctt tgaatcatct ctacagagaa ctgaaatttc ttcttgtttt ggctgatggt ttgaggactg gtgtcactga atggctcgag cccctggaag caaaatctgc tgttgaactt gttcaggaat ttctgaatga cttaaataag ctggatggat ttggtgattc tacaaaaaaa gacactgagg ttgagacctt gaagcatgac actgctgcag tcgatcgttc cgtcaagcgt cttttcaaag ttcggagtga tcttgatttt gctgagcaac tgtggtgcaa aatgagcagt agtgtgattt cataccaaga cttggtgaag tgtttcacat tgatcatcca gagtctacaa cgtggtgata tacagccatg gctccatagt ggaagtaaca gtttactaag taagctcatt catcagtctt atcatggaac catggacaca gtttctctca gtgggactat tccagttcaa atgcttttgg aaattggttt ggacaaacta aagaaagatt atatcagttt tttcataggt caggaacttg catctttgaa tcatttggaa tacttcattg ctccatcagt agatatacaa gaacaggttt atcgtgtcca aaaactccac catattctag aaatattagt cagttgcatg cctttcatta aatctcaaca tgaactcctc ttttctttaa cacagatctg cataaagtat tacaaacaaa atcctcttga tgagcaacac atttttcagc tgccagtcag accaactgct gtaaagaact tatatcaaag tgagaagcca cagaaatgga gagtggaaat atatagtggt caaaagaaga ttaagacagt ttggcaactg agtgacagct cacccataga ccatctgaat tttcacaaac ctgatttttc ggaattaaca ctaaacggta gcctggaaga aaggatattc tttactaaca tggttacctg cagccaggtg catttcaagt gaagtgtgct gatgaagtcc tctataagca caagccaaaa agagaaagag aaaaaaaggt aattattgta gaacctgaaa acagcaatgt atggaaaccc tcaaagcaga aaagggagga agatcctgaa gattctctta tgaagctcca aaattgataa tcctgtctca gctctgcctc ctcaggagga gcattagtag aacagcagtg atgaggacac agagggagca gacagtgggt accacgatct ccgtaaccat ttgcatgtga cttagcaagg gctctgaaat gacaaagaga acgagcacca caaatgagaa caggatcatt ttagtaaata cagctttatc ccaaaagctt taactgtatt gggaaaactt aaaaaatagc atcctcaaat tttctgattc ttatttgcca tgaaatagaa cttagtaaat taaatgttat ttgaaaatgt tataagagct ttgtaaatat ttcagaaaat atgggataaa tgcctgaatt tggttcttct acaggtgcta taataaagtc catctctcaa tacttatact ttctaaattc atctcagaat attagcagcc atattccaca gttcctataa tttttactgg gggggatttg tgataggaaa gtccttggga aacatttcca atctttcaaa atattattgt gtatcttaag aagtatagga acttgtatgt tgaaatgttg tatggtagtt cttgtatagt taaataataa tctttttaag agttaatgat aagcatatgt tatgtgcatt attaataaaa tagtggccac ttaggtaata cccactttta tcttgtgtgc tgggtactct ggttactgag ataaataagg cactggacat cctcacgtgg agttcacagg ctcatcagtg aattctgtac cacatttcaa ccttgtttat tttagtttaa tggaatatac attcttagta ttgcctgatt atttaaattt gttgaggggg attgcatgtt gctttattgg cctgtaaaaa tagctagttt ggtaagattt ggtctcgcac cttccatctt tgctaccaca ttaaagatga gcttgttaaa aaggaaagca tatttctctg attgccctta tggagaaata aagataaaat tcaaagaaac aaaaaaaaaa aaaa SEQ ID NO: 60 Homo sapiens Zwilch, kinetochore associated, homolog (Drosophila) (ZWILCH) (NP_060445.3) MWERLNCAAEDFYSRLLQKFNEEKKGIRKDPFLYEADVQVQLISKGQPNPLKNILNENDIVFIVEKVPLEKEETS HIEELQSEETAISDFSTGENVGPLALPVGKARQLIGLYTMAHNPNMTHLKINLPVTALPPLWVRCDSSDPEGTCW LGAELITTNNSITGIVLYVVSCKADKNYSVNLENLKNLHKKRHHLSTVTSKGFAQYELFKSSALDDTITASQTAI ALDISWSPVDEILQIPPLSSTATLNIKVESGEPRGPLNHLYRELKFLLVLADGLRTGVTEWLEPLEAKSAVELVQ EFLNDLNKLDGFGDSTKKDTEVETLKHDTAAVDRSVKRLFKVRSDLDFAEQLWCKMSSSVISYQDLVKCFTLIIQ SLQRGDIQPWLHSGSNSLLSKLIHQSYHGTMDTVSLSGTIPVQMLLEIGLDKLKKDYISFFIGQELASLNHLEYF IAPSVDIQEQVYRVQKLHHILEILVSCMPFIKSQHELLFSLTQICIKYYKQNPLDEQHIFQLPVRPTAVKNLYQS EKPQKWRVEIYSGQKKIKTVWQLSDSSPIDHLNFHKPDFSELTLNGSLEERIFFTNMVTCSQVHFK SEQ ID NO: 61 Homo sapiens pelota homolog (Drosophila) (PELO)(NM_015946) gatttggccc ggagaacgag atcaccctct caatgaaagg cagatgtccc tttaaggttt gcttctacag cccgtggact ttagcctaaa cacggacccg cgaagctggc tttatttgtc catgtctcgg acagagcctg ggaagctgcc agtgagattt cagagaccaa gagcgcgaag gggcgggcga tgtggcaatc cgtctgggat gtgaaaagcg tggagcgcat ttagaggaat tcgacgaaaa cacaggaaat cactcctctc ccgctcctgg gcgccgctgc cactggggca gaggactggg aaccgcggca gcgggataag tggcccagcc agagagcgca gctcccgcgc ccggtcctgc cctgcgaacc agcgcggccc cctggcgctg aggctgctcc ggccatggcc cctcggcccc gcgcccgccc aggggtcgct gtcgcctgct gctggctcct cactgacagg gatggaagag aaaacttagg aagttgaagt ttggcattaa aataaaggac tcgccaccac tctgtgcacc ttcttgaggg agttcattcg tccggagcgc ctcacagctt agtgcgcctg cgcacgcgcg aactgcggcc ccgcctctcc tttggggacg ggagacgtgc gtcgggtcgc gggacggggg ctgcgcatgc gccttcattt cgtcagcccg ctgttgcgtg ctgccagcgg gaactgtgta ggggtagatt ttcgctgcag tgttccccga gcctgttaga cgcagcgcgc cgggagactg agagaggaaa ggatagagga agtgctgccc taggctgcat gagtcgaagc aagcgtgttt ccttcccgcc aggcaagtgc ccttagaaac cgggccccgc ccccttcctg gcctgcattc ccatcccctc tcccggggcg gaggtgagga cctccttggt tcctttggtt ctgtcagtga gccccttcct tggccatgaa gctcgtgagg aagaacatcg agaaggacaa tgcgggccag gtgaccctgg tccccgagga gcctgaggac atgtggcaca cttacaacct cgtgcaggtg ggcgacagcc tgcgcgcctc caccatccgc aaggtacaga cagagtcctc cacgggcagc gtgggcagca accgggtccg cactaccctc actctctgcg tggaggccat cgacttcgac tctcaagcct gccagctgcg ggttaagggg accaacatcc aagagaatga gtatgtcaag atgggggctt accacaccat cgagctggag cccaaccgcc agttcaccct ggccaagaag cagtgggata gtgtggtact ggagcgcatc gagcaggcct gtgacccagc ctggagcgct gatgtggcgg ctgtggtcat gcaggaaggc ctcgcccata tctgcttagt cactcccagc atgaccctca ctcgggccaa ggtggaggtg aacatcccta ggaaaaggaa aggcaattgc tctcagcatg accgggcctt ggagcggttc tatgaacagg tggtccaggc tatccagcgc cacatacact ttgatgttgt aaagtgcatc ctggtggcca gcccaggatt tgtgagggag cagttctgcg actacctgtt tcaacaagca gtgaagaccg acaacaaact gctcctggaa aaccggtcca aatttcttca ggtacatgcc tcctccggac acaagtactc cctgaaagag gccctttgtg accctactgt ggctagccgc ctttcagaca ctaaagctgc tggggaagtc aaagccttgg atgacttcta taaaatgtta cagcatgaac cggatcgagc tttctatgga ctcaagcagg tggagaaggc caatgaagcc atggcaattg acacattgct catcagcgat gagctcttca ggcatcagga tgtagccaca cggagccggt atgtgaggct ggtggacagt gtgaaagaga atgcaggcac cgttaggata ttctctagtc ttcacgtttc tggggaacag ctcagccagt tgactggggt agctgccatt ctccgcttcc ctgttcccga actttctgac caagagggtg attccagttc tgaagaggat taatgattga aacttaaaat tgagacaatc ttgtgtttcc taaactgtta cagtacattt ctcagcatcc ttgtgacaga aagctgcaag aatggcactt tttgattcat acagggattt cttatgtctt tggctacact agatattttg tgattggcaa gacatgtatt taaacaataa actaaaagga aataatctcc acgtactacc atcttgatta aattgtgtaa ttttttatag gaattatgag ttatctgtag tacttggaaa cagaaaatgt gtgtatttaa agacgatgcc tatgcagtat attgtttggg atagattgca aaatttcaca ctgcatgctt tgaaacagtt ttccttagaa aaagcttttg ctatcttatc ctgtttacat tatttcttta ttttaattct gcttggtgtt cttgcattgc atttaatgat cccttttctc cccacctcca cacactacat tttttttaga tttaaatagt tttactattt taaatgattg ccgtacaatt agtagacttg aagacaagtt ttaaatattt ttcttcaaag gcttgttaaa ccaatcatgt taaaaggaaa ttcttggttt tggtttgttg ttgttagcat tagtcatatt tgatttagag ggtaacttaa atcagttatt tttagctttt tagaactttg atctgctagg gattgtcaaa ataatctcct tgaggcatct ttatttttaa aatgagatta aagtatgtga tttgcttgtt atgtggctaa aaaaaaaaaa aaaaaaaaaa a SEQ ID NO: 62 Homo sapiens pelota homolog (Drosophila)(PELO)(NP_057030.3) MKLVRKNIEKDNAGQVTLVPEEPEDMWHTYNLVQVGDSLRASTIRKVQTESSTGSVGSNRVRTTLTLCVEAIDFD SQACQLRVKGTNIQENEYVKMGAYHTIELEPNRQFTLAKKQWDSVVLERIEQACDPAWSADVAAVVMQEGLAHIC LVTPSMTLTRAKVEVNIPRKRKGNCSQHDRALERFYEQVVQAIQRHIHFDVVKCILVASPGFVREQFCDYLFQQA VKTDNKLLLENRSKFLQVHASSGHKYSLKEALCDPTVASRLSDTKAAGEVKALDDFYKMLQHEPDRAFYGLKQVE KANEAMAIDTLLISDELFRHQDVATRSRYVRLVDSVKENAGTVRIFSSLHVSGEQLSQLTGVAAILRFPVPELSD QEGDSSSEED SEQ ID NO: 63 Homo sapiens zinc finger protein 711 (ZNF711)(NM_021998) agacgcagag tagattgtga ttggctcggg ctgcggaacc tcggaaaccc gaatgtgagg accttaaggg atccacagct gccgcccccc gcagccatcc agagcgcggt cacagtccga ctggcggcac ggaggcggcg gcggcggcgg cggcggcagc ggcggcggca gcggcggcgg cagctgtagc tgcagcagca ggtaaagaga gcgttttccc aaagaaaata acatagcaca gaaggaaaaa taaaaagaaa ttgctgcaga ttttacttta tgtgagaaaa tctacaattt cttcgagaca ctcatataaa gatattggtg aatgaacttt gctaagtatg gattcaggcg gtggaagtct tggattgcac acgccagact ctagaatggc ccataccatg attatgcaag attttgtggc tggaatggct ggtactgcac atatcgatgg agaccatatt gttgtttcag ttcctgaagc tgttttagtt tctgatgttg tcacagatga tgggataact cttgatcatg gccttgcagc tgaagttgtc catggacctg atatcatcac agagactgat gtagtaacag aaggtgtgat tgttcctgaa gcggtacttg aagctgatgt tgccattgaa gaggatttag aggaagatga tggtgatcac atcttgactt ctgaactaat tacagaaacc gttagggtac cagagcaggt tttcgtggct gaccttgtta ctggtcctaa tggacactta gaacatgtgg tccaagattg tgtttcagga gtcgactctc ccacaatggt atcagaggag gttcttgtaa ctaattcaga tacagaaact gtgattcaag cagctggagg tgttcctggt tctacagtta ctataaaaac cgaagatgat gatgatgatg atgtcaagag cacttctgaa gactacttaa tgatatcttt ggatgatgtt ggagaaaaat tagagcatat ggggaataca ccattaaaaa ttggcagtga tggttcacaa gaagatgcta aagaagatgg gtttggttct gaagttataa aagtgtatat atttaaagcg gaggctgaag atgatgttga aataggtgga acagaaattg tcacagagag tgagtacacc agtggacatt cagtagctgg agtgcttgac cagagccgaa tgcagcggga gaagatggtt tacatggcag ttaaagattc ttctcaagaa gaagatgata tcagagatga aagaagagtt tcccgaaggt atgaagattg tcaagcatca ggaaatactt tggactcagc attagaaagc agaagtagta cagcagcaca gtaccttcaa atttgtgacg gcattaatac aaataaagta cttaaacaaa aagccaaaaa gaggagaagg ggagaaacca ggcagtggca aacagctgtt ataataggtc ctgatggaca gcccctcaca gtgtaccctt gccatatttg cacaaaaaag tttaaatcca ggggattctt aaaaagacac atgaagaatc atcctgatca tttaatgaga aaaaaatatc agtgtacaga ttgtgacttt acaactaaca agaaagtgag tttccataac cacttagaaa gccataagct cataaacaaa gtcgacaaaa cccatgaatt tacagaatac acacgaagat acagagaggc tagtccactg agttccaata aacttatttt aagagacaag gagccgaaga tgcacaagtg caaatactgt gactatgaaa ctgcagaaca aggactgtta aacaggcatt tgttggccgt tcacagcaag aattttcctc atgtttgtgt tgagtgtggg aagggttttc gacatccttc tgaactcaag aaacatatga gaacccatac tggtgagaag ccatatcagt gtcagtattg tattttcagg tgtgcagatc aatcaaatct gaaaactcac attaagtcta aacatggtaa caatttgcca tataaatgtg agcattgtcc ccaagcattt ggtgatgaga gggagcttca acgccatctg gatttgtttc aaggacataa gacacaccag tgtcctcatt gtgaccataa gagcaccaat tcaagtgacc ttaagcggca catcatatct gtccatacta aggattttcc tcacaaatgt gaggtctgtg ataaaggttt tcatcgtcct tctgagctca aaaagcatag tgatatccat aagggtagga agattcatca gtgcaggcac tgtgacttta aaacatccga tccatttatt cttagtggcc atatcctttc agttcatact aaagatcagc cattgaaatg taaaaggtgc aagagaggat tcagacaaca aaatgagcta aaaaaacata tgaagaccca tactggaagg aagatttacc aatgtgagta ttgtgaatac agcactacag atgcatctgg ctttaaacga catgtgatat caatacatac aaaagactat ccacacaggt gtgaattctg caagaaggga ttccgaagac catcagaaaa aaatcagcat attatgaggc accacaaaga ggctcttatg taataagatc aatataaaga aagaagctat ttaggagata tgatatgcta cttgggagaa aactctcact aactgtctca ccgggtttca aagcttgata ctaaaccatg actttacatt ctttgtatta aagatcttaa aatatttgaa ttcacagggg atcccatagc cctttgaaaa ttacttaaag aatttaagaa gcactataga atggttacag aaaaacttct taagtatctg tgtaatagta ttatatgcat acttaaacta cagaggggaa aagcaaagac aaatacttta tttggctgat tatgttagat acaaatgttt ctgagaagag aatacataat tgagtttagt gatgctttgc tatagcaagc aaacccactt ttatgcaatt ttagaaatgg ggcagggaaa caaaatgtgg tcattcatca gtcacttagt cattgagcct tttatattgt acctggaaat taaattccag caatgacaaa agttttgtgt attcattaaa agaaaactaa ctggaaaaca ggttagatta attcagtact attaaaaaag aattcagagc tgttaatatt ttatcacagg ataggatact taaaatatag cattctgtgc tgagatctaa ggtgaagtct ataaagatta aagttccctt ttttctgatg ttcaagttga ttgttgttca gtatggcata tatgacaaaa gtatatttga gtcaaatgtg gctttctaaa atggatgcaa cattagcgtt gcaaacaaaa tcagcactat atttcttaat gatctaaaga ttaatttgag agaacacagt tttcttaaat attataatgt ctagagtttt tttaggacag tcttagcaag tatgattgtt ctagtcttac ttgctctaat gtttaaaggt gcaattttat gccattattg aaattgattt ttaaaatcta tataccatat gattaacatg cattttcaat atgaggcagt gtttatgcag tatttaacag agcaatctgc tgccaataga gtttggaggt ggatatttag tttacagtgt ataaacttaa aatatgcatc cctttaacaa cgctttgtgt tagcatgctg caaatcaaaa tggcacttaa tattaaaagc tggtttaggg aaattttatg aaaatcctgt tcataaatgt aatgcatatg atatgtactt ttaagtttta gttgcttcat gtttacattc agctgttcaa cataattaaa atgtaatttt acttcatgct atattgtggc tttgtgtttc aaataatgtt cacctttctg tttttgcacc agataagaat cagttccttg agaataaatt ttttatcttt cttaacttca gaatattaaa tttggaatat ctactaaaat tgtgtgttat gtggctgtaa atgatgtaca cgctgtaaaa taagatcgct actgttatgt gggattatta tttctaaatg ttactcattg aaatgagcat acaataaaaa gcatttattg cacttaaaaa aaaaaaaaaa aa SEQ ID NO: 64 Homo sapiens zinc finger protein 711 (ZNF711)(NP_068838.3) MDSGGGSLGLHTPDSRMAHTMIMQDFVAGMAGTAHIDGDHIVVSVPEAVLVSDVVTDDGITLDHGLAAEVVHGPD IITETDVVTEGVIVPEAVLEADVAIEEDLEEDDGDHILTSELITETVRVPEQVFVADLVTGPNGHLEHVVQDCVS GVDSPTMVSEEVLVTNSDTETVIQAAGGVPGSTVTIKTEDDDDDDVKSTSEDYLMISLDDVGEKLEHMGNTPLKI GSDGSQEDAKEDGFGSEVIKVYIFKAEAEDDVEIGGTEIVTESEYTSGHSVAGVLDQSRMQREKMVYMAVKDSSQ EEDDIRDERRVSRRYEDCQASGNTLDSALESRSSTAAQYLQICDGINTNKVLKQKAKKRRRGETRQWQTAVIIGP DGQPLTVYPCHICTKKFKSRGFLKRHMKNHPDHLMRKKYQCTDCDFTTNKKVSFHNHLESHKLINKVDKTHEFTE YTRRYREASPLSSNKLILRDKEPKMHKCKYCDYETAEQGLLNRHLLAVHSKNFPHVCVECGKGFRHPSELKKHMR THTGEKPYQCQYCIFRCADQSNLKTHIKSKHGNNLPYKCEHCPQAFGDERELQRHLDLFQGHKTHQCPHCDHKST NSSDLKRHIISVHTKDFPHKCEVCDKGFHRPSELKKHSDIHKGRKIHQCRHCDFKTSDPFILSGHILSVHTKDQP LKCKRCKRGFRQQNELKKHMKTHTGRKIYQCEYCEYSTTDASGFKRHVISIHTKDYPHRCEFCKKGFRRPSEKNQ HIMRHHKEALM SEQ ID NO: 65 Homo sapiens intersectin 1 (SH3 domain protein) (ITSN1) (NM_003024) gagcgaggga gggagcgaag gaggtagaga agagtggagg cgccagggga gggagcgtag cttggttgct ccgtagtacg gcggctcgcg aggaagaatc ccgagcgggc tccgggacgg acagagaggc gggcggggat ggtgtgcggg gctgcggctc ctgcgtccct cccagcggcg cgtgagcggc actgatttgt ccctggggcg gcagcgcgga cccgcccgga gatgaggcgt cgattagcaa ggtaaaagta acagaaccat ggctcagttt ccaacacctt ttggtggcag cctggatatc tgggccataa ctgtagagga aagagcgaag catgatcagc agttccatag tttaaagcca atatctggat tcattactgg tgatcaagct agaaactttt tttttcaatc tgggttacct caacctgttt tagcacagat atgggcacta gctgacatga ataatgatgg aagaatggat caagtggagt tttccatagc tatgaaactt atcaaactga agctacaagg atatcagcta ccctctgcac ttccccctgt catgaaacag caaccagttg ctatttctag cgcaccagca tttggtatgg gaggtatcgc cagcatgcca ccgcttacag ctgttgctcc agtgccaatg ggatccattc cagttgttgg aatgtctcca accctagtat cttctgttcc cacagcagct gtgccccccc tggctaacgg ggctccccct gttatacaac ctctgcctgc atttgctcat cctgcagcca cattgccaaa gagttcttcc tttagtagat ctggtccagg gtcacaacta aacactaaat tacaaaaggc acagtcattt gatgtggcca gtgtcccacc agtggcagag tgggctgttc ctcagtcatc aagactgaaa tacaggcaat tattcaatag tcatgacaaa actatgagtg gacacttaac aggtccccaa gcaagaacta ttcttatgca gtcaagttta ccacaggctc agctggcttc aatatggaat ctttctgaca ttgatcaaga tggaaaactt acagcagagg aatttatcct ggcaatgcac ctcattgatg tagctatgtc tggccaacca ctgccacctg tcctgcctcc agaatacatt ccaccttctt ttagaagagt tcgatctggc agtggtatat ctgtcataag ctcaacatct gtagatcaga ggctaccaga ggaaccagtt ttagaagatg aacaacaaca attagaaaag aaattacctg taacgtttga agataagaag cgggagaact ttgaacgtgg caacctggaa ctggagaaac gaaggcaagc tctcctggaa cagcagcgca aggagcagga gcgcctggcc cagctggagc gggcggagca ggagaggaag gagcgtgagc gccaggagca agagcgcaaa agacaactgg aactggagaa gcaactggaa aagcagcggg agctagaacg gcagagagag gaggagagga ggaaagaaat tgagaggcga gaggctgcaa aacgggaact tgaaaggcaa cgacaacttg agtgggaacg gaatcgaagg caagaactac taaatcaaag aaacaaagaa caagaggaca tagttgtact gaaagcaaag aaaaagactt tggaatttga attagaagct ctaaatgata aaaagcatca actagaaggg aaacttcaag atatcagatg tcgattgacc acccaaaggc aagaaattga gagcacaaac aaatctagag agttgagaat tgccgaaatc acccatctac agcaacaatt acaggaatct cagcaaatgc ttggaagact tattccagaa aaacagatac tcaatgacca attaaaacaa gttcagcaga acagtttgca cagagattca cttgttacac ttaaaagagc cttagaagca aaagaactag ctcggcagca cctacgagac caactggatg aagtggagaa agaaactaga tcaaaactac aggagattga tattttcaat aatcagctga aggaactaag agaaatacac aataagcaac aactccagaa gcaaaagtcc atggaggctg aacgactgaa acagaaagaa caagaacgaa agatcataga attagaaaaa caaaaagaag aagcccaaag acgagctcag gaaagggaca agcagtggct ggagcatgtg cagcaggagg acgagcatca gagaccaaga aaactccacg aagaggaaaa actgaaaagg gaggagagtg tcaaaaagaa ggatggcgag gaaaaaggca aacaggaagc acaagacaag ctgggtcggc ttttccatca acaccaagaa ccagctaagc cagctgtcca ggcaccctgg tccactgcag aaaaaggtcc acttaccatt tctgcacagg aaaatgtaaa agtggtgtat taccgggcac tgtacccctt tgaatccaga agccatgatg aaatcactat ccagccagga gacatagtca tggttaaagg ggaatgggtg gatgaaagcc aaactggaga acccggctgg cttggaggag aattaaaagg aaagacaggg tggttccctg caaactatgc agagaaaatc ccagaaaatg aggttcccgc tccagtgaaa ccagtgactg attcaacatc tgcccctgcc cccaaactgg ccttgcgtga gacccccgcc cctttggcag taacctcttc agagccctcc acgaccccta ataactgggc cgacttcagc tccacgtggc ccaccagcac gaatgagaaa ccagaaacgg ataactggga tgcatgggca gcccagccct ctctcaccgt tccaagtgcc ggccagttaa ggcagaggtc cgcctttact ccagccacgg ccactggctc ctccccgtct cctgtgctag gccagggtga aaaggtggag gggctacaag ctcaagccct atatccttgg agagccaaaa aagacaacca cttaaatttt aacaaaaatg atgtcatcac cgtcctggaa cagcaagaca tgtggtggtt tggagaagtt caaggtcaga agggttggtt ccccaagtct tacgtgaaac tcatttcagg gcccataagg aagtctacaa gcatggattc tggttcttca gagagtcctg ctagtctaaa gcgagtagcc tctccagcag ccaagccggt cgtttcggga gaagaattta ttgccatgta cacttacgag agttctgagc aaggagattt aacctttcag caaggggatg tgattttggt taccaagaaa gatggtgact ggtggacagg aacagtgggc gacaaggccg gagtcttccc ttctaactat gtgaggctta aagattcaga gggctctgga actgctggga aaacagggag tttaggaaaa aaacctgaaa ttgcccaggt tattgcctca tacaccgcca ccggccccga gcagctcact ctcgcccctg gtcagctgat tttgatccga aaaaagaacc caggtggatg gtgggaagga gagctgcaag cacgtgggaa aaagcgccag ataggctggt tcccagctaa ttatgtaaag cttctaagcc ctgggacgag caaaatcact ccaacagagc cacctaagtc aacagcatta gcggcagtgt gccaggtgat tgggatgtac gactacaccg cgcagaatga cgatgagctg gccttcaaca agggccagat catcaacgtc ctcaacaagg aggaccctga ctggtggaaa ggagaagtca atggacaagt ggggctcttc ccatccaatt atgtgaagct gaccacagac atggacccaa gccagcaatg gtgttcagac ttacatctct tggatatgtt gaccccaact gaaagaaagc gacaaggata catccacgag ctcattgtca ccgaggagaa ctatgtgaat gacctgcagc tggtcacaga gatttttcaa aaacccctga tggagtctga gctgctgaca gaaaaagagg ttgctatgat ttttgtgaac tggaaggagc tgattatgtg taatatcaaa ctactaaaag cgctgagagt ccgcaagaag atgtccgggg agaagatgcc tgtgaagatg attggagaca tcctgagcgc acagctgccg cacatgcagc cctacatccg cttctgcagc cgccagctca acggggctgc cctgatccag cagaagacgg atgaggcccc agacttcaag gagttcgtca aaagattggc aatggatcct cggtgtaaag ggatgccact ctctagtttt atactgaagc ctatgcaacg ggtaacaaga tacccactga tcattaaaaa tatcctggaa aacacccctg aaaaccaccc ggaccacagc cacttgaagc acgccctgga gaaggcggaa gagctctgtt cccaggtgaa cgaaggggtg cgggagaagg agaactctga ccggctggag tggatccagg cccacgtgca gtgtgaaggc ctgtctgagc aacttgtgtt caattcagtg accaattgct tggggccgcg caaatttctg cacagtggga agctctacaa ggccaagagc aacaaggagc tgtatggctt ccttttcaac gacttcctcc tgctgactca gatcacgaag cctttggggt cttctggcac cgacaaagtc ttcagcccca aatcaaacct gcagtataaa atgtataaaa cacctatttt cctaaatgag gttctagtaa aattacccac cgacccttct ggagacgagc ccatcttcca catctcccac attgaccgcg tctatactct ccgagcagaa agcataaatg aaaggactgc ctgggtgcag aaaatcaaag ctgcttctga actctacata gagactgaga aaaagaagcg cgagaaagcg tacctggtcc gttcccaaag ggcaacaggc attggaaggt tgatggtgaa cgtggttgaa ggcatcgagt tgaaaccctg tcggtcacat ggaaagagca acccgtactg tgaggtgacc atgggttccc agtgccacat caccaagacg atccaggaca ctctgaaccc caagtggaat tccaactgcc agttcttcat ccgagacctg gagcaggaag tcctctgcat cactgtgttc gagagggacc agttctcacc agatgatttt ttgggtcgga cggagatccg tgtggcggac atcaagaaag accagggctc caaaggtcca gttacgaagt gtcttctgct gcacgaagtc cccacgggag agattgtggt ccgcttggac ctgcagttgt ttgatgagcc gtaggcagcg ggctcagggt gtgctcagca gggtcccagc ccacggccac acatgctgtc tggaaattgt attccttttc taagaaacca ccatttggta ttcagtcaca gggatatggg atggcaaaga caggcccctc aaagctccta ggaatcattc tcgacaatcc tccctgcccc gaaacaattt cctgtttcat gaaacaaagc tgtgttttcc tttgtcctca ctacaggtct cattatggct tctagggtcg ctgaaatccc atagccctca acagggtgca gctgggagtc tagccccttc ccgggcttga gggatgggtc tggttactat aaaatagatt tataaatgca atgtctatat ttttggagaa ctcatgtaac cctcctgttt cttacatcca ccagtcccca agtagacttc ttggcctaca atgcccagtc cttggtgtga gtttagaaac aattatgacg gtcctgtcat tgcttcagaa tcccatctct cctgcaggga aatgctgcct agagctgatc actcggtgag acggtctgat caggccctgg cttagctctt tgaagagctg gtctatggaa gtttccagca tgtgcaccgt tatagccgtt ccttccccct ctaggccttg tattaatata tgtcaatgaa aacacactgg tgtattgttg cgtggattca gttctgattc ccagcatgct tagaatatgg tcacagaaag tcattatcta gaaagtcacc cctctgctgg atcagatcac tacaggtcac tggaaaggca actttacaat gttgggtcac tgggtctcgg ttggcagcca tgttggaaaa atctcttttg gctcggaggc ctgtgatatt tcatagcagc agtcgttgct ggtgacctgt tctgtgcttg aatgtgctga atcctgattg ttgtaggaca tttcaacagc tctttttggt acgttcccca aaaagccatg tcctagatcc ccaaggcgt SEQ ID NO: 66 Homo sapiens intersectin 1 (SH3 domain protein) (ITSN1) (NP_003015.2) MAQFPTPFGGSLDIWAITVEERAKHDQQFHSLKPISGFITGDQARNFFFQSGLPQPVLAQIWALADMNNDGRMDQ VEFSIAMKLIKLKLQGYQLPSALPPVMKQQPVAISSAPAFGMGGIASMPPLTAVAPVPMGSIPVVGMSPTLVSSV PTAAVPPLANGAPPVIQPLPAFAHPAATLPKSSSFSRSGPGSQLNTKLQKAQSFDVASVPPVAEWAVPQSSRLKY RQLFNSHDKTMSGHLTGPQARTILMQSSLPQAQLASIWNLSDIDQDGKLTAEEFILAMHLIDVAMSGQPLPPVLP PEYIPPSFRRVRSGSGISVISSTSVDQRLPEEPVLEDEQQQLEKKLPVTFEDKKRENFERGNLELEKRRQALLEQ QRKEQERLAQLERAEQERKERERQEQERKRQLELEKQLEKQRELERQREEERRKEIERREAAKRELERQRQLEWE RNRRQELLNQRNKEQEDIVVLKAKKKTLEFELEALNDKKHQLEGKLQDIRCRLTTQRQEIESTNKSRELRIAEIT HLQQQLQESQQMLGRLIPEKQILNDQLKQVQQNSLHRDSLVTLKRALEAKELARQHLRDQLDEVEKETRSKLQEI DIFNNQLKELREIHNKQQLQKQKSMEAERLKQKEQERKIIELEKQKEEAQRRAQERDKQWLEHVQQEDEHQRPRK LHEEEKLKREESVKKKDGEEKGKQEAQDKLGRLFHQHQEPAKPAVQAPWSTAEKGPLTISAQENVKVVYYRALYP FESRSHDEITIQPGDIVMVKGEWVDESQTGEPGWLGGELKGKTGWFPANYAEKIPENEVPAPVKPVTDSTSAPAP KLALRETPAPLAVTSSEPSTTPNNWADFSSTWPTSTNEKPETDNWDAWAAQPSLTVPSAGQLRQRSAFTPATATG SSPSPVLGQGEKVEGLQAQALYPWRAKKDNHLNFNKNDVITVLEQQDMWWFGEVQGQKGWFPKSYVKLISGPIRK STSMDSGSSESPASLKRVASPAAKPVVSGEEFIAMYTYESSEQGDLTFQQGDVILVTKKDGDWWTGTVGDKAGVF PSNYVRLKDSEGSGTAGKTGSLGKKPEIAQVIASYTATGPEQLTLAPGQLILIRKKNPGGWWEGELQARGKKRQI GWFPANYVKLLSPGTSKITPTEPPKSTALAAVCQVIGMYDYTAQNDDELAFNKGQIINVLNKEDPDWWKGEVNGQ VGLFPSNYVKLTTDMDPSQQWCSDLHLLDMLTPTERKRQGYIHELIVTEENYVNDLQLVTEIFQKPLMESELLTE KEVAMIFVNWKELIMCNIKLLKALRVRKKMSGEKMPVKMIGDILSAQLPHMQPYIRFCSRQLNGAALIQQKTDEA PDFKEFVKRLAMDPRCKGMPLSSFILKPMQRVTRYPLIIKNILENTPENHPDHSHLKHALEKAEELCSQVNEGVR EKENSDRLEWIQAHVQCEGLSEQLVFNSVTNCLGPRKFLHSGKLYKAKSNKELYGFLFNDFLLLTQITKPLGSSG TDKVFSPKSNLQYKMYKTPIFLNEVLVKLPTDPSGDEPIFHISHIDRVYTLRAESINERTAWVQKIKAASELYIE TEKKKREKAYLVRSQRATGIGRLMVNVVEGIELKPCRSHGKSNPYCEVTMGSQCHITKTIQDTLNPKWNSNCQFF IRDLEQEVLCITVFERDQFSPDDFLGRTEIRVADIKKDQGSKGPVTKCLLLHEVPTGEIVVRLDLQLFDEP SEQ ID NO: 67 Homo sapiens phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1) (NM_021127) actggacaaa agcgtggtct ctggcgcggg gatctcagag tttcccgggc actcaccgtg tgtagttggc atctccgcgc gtccggacac ccgatcccag catccctgcc tgcaggactg ttcgtgttca gctcgcgtcc tgcagctgtc cgaggtgctc cagttggagg ctgaggttcc cgggctctgt agctgagtgg gcggcggcac cggcggagat gcctgggaag aaggcgcgca agaacgctca accgagcccc gcgcgggctc cagcagagct ggaagtcgag tgtgctactc aactcaggag atttggagac aaactgaact tccggcagaa acttctgaat ctgatatcca aactcttctg ctcaggaacc tgactgcatc aaaaacttgc atgaggggac tccttcaaaa gagttttctc aggaggtgca cgtttcatca atttgaagaa agactgcatt gtaattgaga ggaatgtgaa ggtgcattca tgggtgccct tggaaacgga agatggaata catcaaagtg aatttctgtt caagttttcc cagattatca ttctttggga tgagagaaca ttataaaacc actttgttta ttttaaagca agaatggaag acccttgaaa ataaagaagt aattattgac acatttcttt tttacttaga gaatcgttct agtgtttttg ccgaagatta ccgctggcct actgtgaagg gagatgacct gtgattagac tgggcggctg gggagaaaca gttcagtgca ttgttgttgt tgctgttttt ggtgttttgc ttttcagtgc caactcagca cattgtatat gattcggttt atacatatta ccttgttata atgaaaaaac tcattctgag aacactgaaa tgttatactc agtgttgatt tcttcggtca ctacacaacg taaaatcatt tgtttctttt gactcaaatt gtattgcttc tgttcagatg atctttcatt caatgtgttc ctgttgggcg ttactagaaa ctatggaaaa ctggaaaata actttgaaaa aattggataa agtataggag ggttacttgg ggccagtaaa tcagtagact gaacattcaa tataataaaa gaacatgggg attttgtata accagggata ataaaaagaa aaaagaagtt aatttttaat tgatgttttt gaaacttagt agaacaaata ttcagaagta acttgataag atatgaatgt ttctaaagaa gtttctaaag gttcggaaaa tgctccttgt cacattagtg tgcatcctac aaaaagtgat ctcttaatgt aaattaagaa tattttcata attggaatat acttttctta aaaaaaagga acagttagtt ctcatctaga atgaaagttc catatatgca ttggtgaata tatatgtata cacatactta catacttata tgggtatctg tatagataat ttgtattaga gtattatata gcttcttagt agggtctcaa gtaagtttca ttttttttat ctgggctata tacagtcctc aaataaataa tgtcttgatt ttatttcagc aggaataatt ttatttattt tgcctattta taattaaagt atttttcttt agtttgaaaa tgtgtattaa agttacattt ttgagttaca agagtcttat aactacttga atttttagtt aaaatgtctt aatgtaggtt gtagtcactt tagatggaaa attacctcac atctgttttc ttcagtatta cttaagattg tttatttagt ggtagagagt tttttttttc agcctagagg cagctatttt accatctggt atttatggtc taatttgtat ttaaacatat gcacacatat aaaagttgat actgtggcag taaactatta aaagttttca ctgttcaaaa aaaaaaaaaa aaaa SEQ ID NO: 68 Homo sapiens phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1) (NP_066950.1) MPGKKARKNAQPSPARAPAELEVECATQLRRFGDKLNFRQKLLNLISKLFCSGT SEQ ID NO: 69 Homo sapiens transmembrane protein 47 (TMEM47) (NM_031442) ggcagagcgc ggcgcggggc cggcggcgaa ggtccggggt ggaatcgacg tcgctgcggc tgccgacgac ccacacccgg ccggccgcct ccgcagaccc accttggccg cgcggcaggg ggcgcgcaga gccccgaggg agcgagtccc cgcgcgtggc agctcggcgg cttctccctt cgggaggtcc ggctcccggc tctccggacc cgcctggcgt cctcgcctgc ggcggggcgg acgacagcgg cgcccaggaa tggcttcggc gggcagcggc atggaggagg tgcgcgtgtc ggtgctgacc cccttgaagc tggtcgggct ggtgtgcatc ttcctggcgc tgtgtctgga cctgggggcg gtgctgagcc cggcctgggt cacagctgac caccagtact acctgtcgtt gtgggagtcc tgccgcaaac ccgccagctt ggacatctgg cactgcgagt ccacgctcag cagcgattgg cagattgcta ctctggcttt actcctgggc ggcgctgcca tcattctcat tgcattcctg gtgggtttga tttctatctg cgtgggatct cgaaggcgtt tctatagacc tgttgcggtc atgctttttg cagcagttgt tttacaggtt tgcagcctgg tcctttaccc aatcaagttc attgaaactg tgagcttgaa aatttaccat gagttcaact ggggttatgg cctggcctgg ggtgcaacta tattttcgtt tgggggtgcc atcctttatt gcctgaaccc taagaactat gaagactact actagaacca atagtctcaa agtaaaaaca accaccacca tccaacaaaa ggattacgtc tgcatctttt ctaacttact attttctaaa acacttgtgg agcatcaagc agtttgctca gttgatttaa tcttttttgc cttttggctg tcaacatcat aaccagcttt tacatccatt ttagaaatct gcacaaatta agagagctga ttagacatag gcaaatgctg caaacttcca atatgttcat atcgtttttc ttgacaaatg aagggtctat atgacagcaa ccattgtgag aaactagttg gaatgagatt tgcctcaatc tcctattgcc tgcaggggag cagttggcat aagcaacatt tagaagttcc tttgcgctga caaggattcc actgttagag cccttaccgc ctgcttatcc tacccaatga ctacattggc tgttggttat ttgcttgagt gagcccttga aaaatgaact gcccttcagc atctaatggg agttgtgaat gtaactggtt aatgatacac attccacctt caggaacact ctttttaatg ggaggttatg ctttggcaat cagcgtctcc ctgggaagag agtcaagact tggagacatg tgcttctcat tatgtggtta gaaattggtg cctcagccct atctagactg gggaaaaatt gaggatctct gtttttcctg gggcaaacag aaagaaatct gcatgagttg cttttgtacc ctttaaatca tttgccaaac attgcagcaa acaagtgtgc gtatgtaaca agcttcactg tttttataga aggtgaacca ttagtataaa tggtaataag ttgttcccta accctccaca tacatttgcc tatcacacgt aaaattaata tttactctag tgaagtggtt tgagcactaa ccttgtacac attgttaaga ggcttagatt ggtattcata cttatttacc atacaaaagt atggtacctt aaagcttttg ctctatgttc tttactgttt cactggaaag tgtcaataga gttgcctaag aataaaaatt gaaatggtgt taatctgaaa attaatgatt ctctgtaagc actgtagttg aaaagagagt agcaattagg atgatcattt tgtgtaaaat tcattaaaat agaaggctgc tattttttgc aagtatttta aatgtcttca tttttttaag aaaggaatag cgatagattt atataaatat ctaaatgtct cagtagagga gtagaattca tctggttatc acctggtcct ctgaagttaa ctgatgggct aaccgatttg tgcacacact taggatggat ttatgttaag ggaattactt actgactgtt caatggaagg aagtattaat aatagggaat aagtttgcaa ctaatctcat gctgcaaact tgtgttaatt ctgtttaata tacaaatttg gatagcttaa ttataaacat atttttatat caaatataca gttctaatat aaaagttata aataattatt tttgttaaca aagacactaa aacagtatgt tctggttttg gccctcttgc agaaagaagc attagaaaaa ttactttaaa agtagctata tgttactgta ttgcaaaatc tgttaagagc aggaccacat cgatagtatt taataatttg ttttacctcc caaaacacag ttcttctttc agcttgtctt aagaatggtt gccaaaaaca acagccaaaa aaaaaaaacc tattttatta tccaaatgct agaaaacaca catgaatttt ctataaaatc acgaatatga agtaccaggt ttagtcttac tttagcaatg atagacaaaa gcgaataaat acatcacaga cagaaacctt tataaaaata tatgattcta taaagaatca ttagaaatta tgagtggaaa ttctccagaa agatagtatt atagagtctt ttgaagcaat tttttgagaa atagtaaaat ctggggcaga gtgtcttgca gttaattgca tattgtcaga gcagcatgag aaatatgata tttggatagg gatttcagca actaaacatt ctctgttctg agatctcttt attcctgaat aatgaaagaa tagtactttg gtgctgacac caatgaggca cttctcttgg tcctagtaga ggatgcagtg tactgttaaa ccaatatcat cacatctcga gtcttatcaa gttttcattc tctgtcaata tgacaagctc aaagtgacag aatatgttat aggttgaagc acacatattt gcagtttact gaaaagtaga tttcttatgt gacttttttc ccttctcagc aaagagccct acactagatt tctaccatca ctaatatttg gaagtatttc attactaaca atctcagtac aacatgaaaa ttgttgcttc tcatctaaaa tacaattttg tctatcagaa taaacacaag tgaaattttc acctacatta acattatgtc tttgcagctt taggtttgtt agatgtgttc ttaagcataa tttttagcca caaacccatt gttagataga tatctatgga tatagatcta catctataga tatagatata cacacatata tatactcaca cacatatagc ataaaatact cagcagggct agttattccg atttcttgca caattattta gctttttgta agttcaacat gtaaatttta aagacataaa tatagagaga cttatgtgtt tgaatataaa tgatatatat ggattagcat gtacctgtat attattaaac atgcaatgaa ctgactggta agtgacgtct aattgtatgg ctagcaatgt aatttattca gactgtattt ttgtacagag cagtgcactc taacctatgc ctctgtgtcc tctttaatgc ctaaagctgt gcctagaaat ttcatctgtc ttaaaagtaa aatatacttc atgctgttta tgctattagt ttctgtactg ctattctata tttattattt ttaaatatat gacatgttta ctacttaaac atgaattcat ggtatcctgg ttattttttt taagtcatct gggggaaaac ctgtttatca ctccagtgat tttgagtttg cagtttcaca atcagttctt catttcatga tttttgtagt tgacatgaag tcatctatgt ggaaaaaaat aaaaataaaa gtgatttcac ggatgtggtt tgaaaaaaaa aaaaaaaa SEQ ID NO: 70 Homo sapiens transmembrane protein 47 (TMEM47)(NP_113630.1) MASAGSGMEEVRVSVLTPLKLVGLVCIFLALCLDLGAVLSPAWVTADHQYYLSLWESCRKPASLDIWHCESTLSS DWQIATLALLLGGAAIILIAFLVGLISICVGSRRRFYRPVAVMLFAAVVLQVCSLVLYPIKFIETVSLKIYHEFN WGYGLAWGATIFSFGGAILYCLNPKNYEDYY SEQ ID NO: 71 Homo sapiens interleukin 11 (IL11)(NM_000641) gctcagggca catgcctccc ctccccaggc cgcggcccag ctgaccctcg gggctccccc ggcagcggac agggaagggt taaaggcccc cggctccctg ccccctgccc tggggaaccc ctggccctgt ggggacatga actgtgtttg ccgcctggtc ctggtcgtgc tgagcctgtg gccagataca gctgtcgccc ctgggccacc acctggcccc cctcgagttt ccccagaccc tcgggccgag ctggacagca ccgtgctcct gacccgctct ctcctggcgg acacgcggca gctggctgca cagctgaggg acaaattccc agctgacggg gaccacaacc tggattccct gcccaccctg gccatgagtg cgggggcact gggagctcta cagctcccag gtgtgctgac aaggctgcga gcggacctac tgtcctacct gcggcacgtg cagtggctgc gccgggcagg tggctcttcc ctgaagaccc tggagcccga gctgggcacc ctgcaggccc gactggaccg gctgctgcgc cggctgcagc tcctgatgtc ccgcctggcc ctgccccagc cacccccgga cccgccggcg cccccgctgg cgcccccctc ctcagcctgg gggggcatca gggccgccca cgccatcctg ggggggctgc acctgacact tgactgggcc gtgaggggac tgctgctgct gaagactcgg ctgtgacccg gggcccaaag ccaccaccgt ccttccaaag ccagatctta tttatttatt tatttcagta ctgggggcga aacagccagg tgatcccccc gccattatct ccccctagtt agagacagtc cttccgtgag gcctgggggg catctgtgcc ttatttatac ttatttattt caggagcagg ggtgggaggc aggtggactc ctgggtcccc gaggaggagg ggactggggt cccggattct tgggtctcca agaagtctgt ccacagactt ctgccctggc tcttccccat ctaggcctgg gcaggaacat atattattta tttaagcaat tacttttcat gttggggtgg ggacggaggg gaaagggaag cctgggtttt tgtacaaaaa tgtgagaaac ctttgtgaga cagagaacag ggaattaaat gtgtcataca tatccacttg agggcgattt gtctgagagc tggggctgga tgcttgggta actggggcag ggcaggtgga ggggagacct ccattcaggt ggaggtcccg agtgggcggg gcagcgactg ggagatgggt cggtcaccca gacagctctg tggaggcagg gtctgagcct tgcctggggc cccgcactgc atagggcctt ttgtttgttt tttgagatgg agtctcgctc tgttgcctag gctggagtgc agtgaggcaa tctgaggtca ctgcaacctc cacctcccgg gttcaagcaa ttctcctgcc tcagcctccc gattagctgg gatcacaggt gtgcaccacc atgcccagct aattatttat ttcttttgta tttttagtag agacagggtt tcaccatgtt ggccaggctg gtttcgaact cctgacctca ggtgatcctc ctgcctcggc ctcccaaagt gctgggatta caggtgtgag ccaccacacc tgacccatag gtcttcaata aatatttaat ggaaggttcc acaagtcacc ctgtgatcaa cagtacccgt atgggacaaa gctgcaaggt caagatggtt cattatggct gtgttcacca tagcaaactg gaaacaatct agatatccaa cagtgagggt taagcaacat ggtgcatctg tggatagaac gccacccagc cgcccggagc agggactgtc attcagggag gctaaggaga gaggcttgct tgggatatag aaagatatcc tgacattggc caggcatggt ggctcacgcc tgtaatcctg gcactttggg aggacgaagc gagtggatca ctgaagtcca agagttcgag accggcctgc gagacatggc aaaaccctgt ctcaaaaaag aaagaatgat gtcctgacat gaaacagcag gctacaaaac cactgcatgc tgtgatccca attttgtgtt tttctttcta tatatggatt aaaacaaaaa tcctaaaggg aaatacgcca aaatgttgac aatgactgtc tccaggtcaa aggagagagg tgggattgtg ggtgactttt aatgtgtatg attgtctgta ttttacagaa tttctgccat gactgtgtat tttgcatgac acattttaaa aataataaac actattttta gaat SEQ ID NO: 72 Homo sapiens interleukin 11 (IL11)(NP_000632.1) MNCVCRLVLVVLSLWPDTAVAPGPPPGPPRVSPDPRAELDSTVLLTRSLLADTRQLAAQLRDKFPADGDHNLDSL PTLAMSAGALGALQLPGVLTRLRADLLSYLRHVQWLRRAGGSSLKTLEPELGTLQARLDRLLRRLQLLMSRLALP QPPPDPPAPPLAPPSSAWGGIRAAHAILGGLHLTLDWAVRGLLLLKTRL SEQ ID NO: 73 Homo sapiens chemokine (C motif) ligand 2 (XCL2)(NM_003175) agctcagcgg gacctcagcc atgagacttc tcatcctggc cctccttggc atctgctctc tcactgcata cattgtggaa ggtgtaggga gtgaagtctc acataggagg acctgtgtga gcctcactac ccagcgactg ccagttagca gaatcaagac ctacaccatc acggaaggct ccttgagagc agtaattttt attaccaaac gtggcctaaa agtctgtgct gatccacaag ccacgtgggt gagagacgtg gtcaggagca tggacaggaa atccaacacc agaaataaca tgatccagac caagccaaca ggaacccagc aatcgaccaa tacagctgtg accctgactg gctagtagtc tctggcaccc tgtccgtctc cagccagcca gctcatttca ctttacaccc tcatggactg agattatact caccttttat gaaagcactg catgaataaa attattcctt tgtattttta cttttaaatg tcttctgtat tcacttatat gttctaatta ataaattatt tattattaag aa SEQ ID NO: 74 Homo sapiens chemokine (C motif) ligand 2 (XCL2)(NP_003166.1) MRLLILALLGICSLTAYIVEGVGSEVSHRRTCVSLTTQRLPVSRIKTYTITEGSLRAVIFITKRGLKVCADPQAT WVRDVVRSMDRKSNTRNNMIQTKPTGTQQSTNTAVTLTG SEQ ID NO: 74 Homo sapiens prostaglandin E receptor 4 (subtype EP4) (PTGER4) (NM_000958) gcgagagcgg agctccaagc ccggcagccc gagaggaaga tgaacagccc caggccagag cctctggcag agtggacccc gagccgcccc caggtagcca ggagcggcct cagcggcagc cgcaaactcc agtagccgcc cgtgctgccc gtggctgggg cggagggcag ccagagctgg ggaccaaggc tccgcgccac ctgcgcgcac agcctcacac ctgaacgctg tcctcccgca gacgagaccg gcgggcactg caaagctggg actcgtcttt gaaggaaaaa aaatagcgag taagaaatcc agcaccattc ttcactgacc catcccgctg cacctcttgt ttcccaagtt tttgaaagct ggcaactctg acctcggtgt ccaaaaatcg acagccactg agaccggctt tgagaagccg aagatttggc agtttccaga ctgagcagga caaggtgaaa gcaggttgga ggcgggtcca ggacatctga gggctgaccc tgggggctcg tgaggctgcc accgctgctg ccgctacaga cccagccttg cactccaagg ctgcgcaccg ccagccacta tcatgtccac tcccggggtc aattcgtccg cctccttgag ccccgaccgg ctgaacagcc cagtgaccat cccggcggtg atgttcatct tcggggtggt gggcaacctg gtggccatcg tggtgctgtg caagtcgcgc aaggagcaga aggagacgac cttctacacg ctggtatgtg ggctggctgt caccgacctg ttgggcactt tgttggtgag cccggtgacc atcgccacgt acatgaaggg ccaatggccc gggggccagc cgctgtgcga gtacagcacc ttcattctgc tcttcttcag cctgtccggc ctcagcatca tctgcgccat gagtgtcgag cgctacctgg ccatcaacca tgcctatttc tacagccact acgtggacaa gcgattggcg ggcctcacgc tctttgcagt ctatgcgtcc aacgtgctct tttgcgcgct gcccaacatg ggtctcggta gctcgcggct gcagtaccca gacacctggt gcttcatcga ctggaccacc aacgtgacgg cgcacgccgc ctactcctac atgtacgcgg gcttcagctc cttcctcatt ctcgccaccg tcctctgcaa cgtgcttgtg tgcggcgcgc tgctccgcat gcaccgccag ttcatgcgcc gcacctcgct gggcaccgag cagcaccacg cggccgcggc cgcctcggtt gcctcccggg gccaccccgc tgcctcccca gccttgccgc gcctcagcga ctttcggcgc cgccggagct tccgccgcat cgcgggcgcc gagatccaga tggtcatctt actcattgcc acctccctgg tggtgctcat ctgctccatc ccgctcgtgg tgcgagtatt cgtcaaccag ttatatcagc caagtttgga gcgagaagtc agtaaaaatc cagatttgca ggccatccga attgcttctg tgaaccccat cctagacccc tggatatata tcctcctgag aaagacagtg ctcagtaaag caatagagaa gatcaaatgc ctcttctgcc gcattggcgg gtcccgcagg gagcgctccg gacagcactg ctcagacagt caaaggacat cttctgccat gtcaggccac tctcgctcct tcatctcccg ggagctgaag gagatcagca gtacatctca gaccctcctg ccagacctct cactgccaga cctcagtgaa aatggccttg gaggcaggaa tttgcttcca ggtgtgcctg gcatgggcct ggcccaggaa gacaccacct cactgaggac tttgcgaata tcagagacct cagactcttc acagggtcag gactcagaga gtgtcttact ggtggatgag gctggtggga gcggcagggc tgggcctgcc cctaagggga gctccctgca agtcacattt cccagtgaaa cactgaactt atcagaaaaa tgtatataat aggcaaggaa agaaatacag tactgtttct ggacccttat aaaatcctgt gcaatagaca catacatgtc acatttagct gtgctcagaa gggctatcat catcctacaa ctcacattag agaacatcct ggcttttgag cacttttcaa acaatcaagt tgactcacgt gggtcctgag gcctgcagca cgtcggatgc taccccacta tgacagagga ttgtggtcac aacttgatgg ctgcgaagac ctaccctccg tttttctact agataggagg atggtagaag tttggctgct gtcataacat ccagagcttt gtcgtatttg gcacacagca gaggcccaga tattagaaag gctctattcc aataaactat gaggactgcc ttatggatga tttaagtgtc tcactaaagc atgaaatgtg aatttttatt gttgtacata cgatttaagg tatttaaagt attttcttct ctgtgagaag gtttattgtt aatacaaggt ataataaaat tatcgcaacc cctctccttc cagtataacc agctgaagtt gcagatgtta gatatttttc ataaacaagt tcgagtcaaa gttgaaaatt catagtaaga ttgatatcta taaaatagat ataaattttt aagagaaaga atttagtatt atcaaaggga taaagaaaaa aatactattt aagatgtgaa aattacagtc caaaatactg ttctttccag gctatgtata aaatacatag tgaaaattgt ttagtgatat tacatttatt tatccagaaa actgtgattt caggagaacc taacatgctg gtgaatattt tcaacttttt ccctcactaa ttggtacttt taaaaacata acataaattt tttgaagtct ttaataaata acccataatt gaagtgtata atataaaaaa ttttaaaaat ctaagcagct tattgtttct ctgaaagtgt gtgtagtttt actttcctaa ggaattacca agaatatcct ttaaaattta aaaggatggc aagttgcatc agaaagcttt attttgagat gtaaaaagat tcccaaacgt ggttacatta gccattcatg tatgtcagaa gtgcagaatt ggggcactta atggtcacct tgtaacagtt ttgtgtaact cccagtgatg ctgtacacat atttgaaggg tctttctcaa agaaatatta agcatgtttt gttgctcagt gtttttgtga attgcttggt tgtaattaaa ttctgagcct gatattgata tggttttaag aagcagttgt accaagtgaa attattttgg agattataat aaatatatac attcaaaaaa aaaaaaaaaa aa SEQ ID NO: 76 Homo sapiens prostaglandin E receptor 4 (subtype EP4) (PTGER4) (NP_000949.1) MSTPGVNSSASLSPDRLNSPVTIPAVMFIFGVVGNLVAIVVLCKSRKEQKETTFYTLVCGLAVTDLLGTLLVSPV TIATYMKGQWPGGQPLCEYSTFILLFFSLSGLSIICAMSVERYLAINHAYFYSHYVDKRLAGLTLFAVYASNVLF CALPNMGLGSSRLQYPDTWCFIDWTTNVTAHAAYSYMYAGFSSFLILATVLCNVLVCGALLRMHRQFMRRTSLGT EQHHAAAAASVASRGHPAASPALPRLSDFRRRRSFRRIAGAEIQMVILLIATSLVVLICSIPLVVRVFVNQLYQP SLEREVSKNPDLQAIRIASVNPILDPWIYILLRKTVLSKAIEKIKCLFCRIGGSRRERSGQHCSDSQRTSSAMSG HSRSFISRELKEISSTSQTLLPDLSLPDLSENGLGGRNLLPGVPGMGLAQEDTTSLRTLRISETSDSSQGQDSES VLLVDEAGGSGRAGPAPKGSSLQVTFPSETLNLSEKCI SEQ ID NO: 77 Homo sapiens caspase 2, apoptosis-related cysteine peptidase (neural precursor cell expressed, developmentally down-regulated 2) (CASP2) (NM_032982) gggtggcctg gtgtgtgggc gcggcagggc gcaggcgcag gcgcagtgtg cgtccgcgtc tgaggggagg gatgtggggg aagcgacggc ccccggtttg tttgggctgt gggcggtgcg cagcggagag cccgggaaaa gcgggaaatg gcggcgccga gcgcggggtc ttggtccacc ttccagcaca aggagctgat ggccgctgac aggggacgca ggatattggg agtgtgtggc atgcatcctc atcatcagga aactctaaaa aagaaccgag tggtgctagc caaacagctg ttgttgagcg aattgttaga acatcttctg gagaaggaca tcatcacctt ggaaatgagg gagctcatcc aggccaaagt gggcagtttc agccagaatg tggaactcct caacttgctg cctaagaggg gtccccaagc ttttgatgcc ttctgtgaag cactgaggga gaccaagcaa ggccacctgg aggatatgtt gctcaccacc ctttctgggc ttcagcatgt actcccaccg ttgagctgtg actacgactt gagtctccct tttccggtgt gtgagtcctg tcccctttac aagaagctcc gcctgtcgac agatactgtg gaacactccc tagacaataa agatggtcct gtctgccttc aggtgaagcc ttgcactcct gaattttatc aaacacactt ccagctggca tataggttgc agtctcggcc tcgtggccta gcactggtgt tgagcaatgt gcacttcact ggagagaaag aactggaatt tcgctctgga ggggatgtgg accacagtac tctagtcacc ctcttcaagc ttttgggcta tgacgtccat gttctatgtg accagactgc acaggaaatg caagagaaac tgcagaattt tgcacagtta cctgcacacc gagtcacgga ctcctgcatc gtggcactcc tctcgcatgg tgtggagggc gccatctatg gtgtggatgg gaaactgctc cagctccaag aggtttttca gctctttgac aacgccaact gcccaagcct acagaacaaa ccaaaaatgt tcttcatcca ggcctgccgt ggagatgaga ctgatcgtgg ggttgaccaa caagatggaa agaaccacgc aggatcccct gggtgcgagg agagtgatgc cggtaaagaa aagttgccga agatgagact gcccacgcgc tcagacatga tatgcggcta tgcctgcctc aaagggactg ccgccatgcg gaacaccaaa cgaggttcct ggtacatcga ggctcttgct caagtgtttt ctgagcgggc ttgtgatatg cacgtggccg acatgctggt taaggtgaac gcacttatca aggatcggga aggttatgct cctggcacag aattccaccg gtgcaaggag atgtctgaat actgcagcac tctgtgccgc cacctctacc tgttcccagg acaccctccc acatgatgtc acctccccat catccacgcc aagtggaagc cactggacca caggaggtgt gatagagcct ttgatcttca ggatgcacgg tttctgttct gccccctcag ggatgtggga atctcccaga cttgtttcct gtgcccatca tctctgcctt tgagtgtggg actccaggcc agctcctttt ctgtgaagcc ctttgcctgt agagccagcc ttggttggac ctattgccag gaatgtttca gctgcagttg aagagcctga caagtgaagt tgtaaacaca gtgtggttat ggggagaggg catataaatt ccccatattt gtgttcagtt ccagcttttg tagatggcac tttagtgatt gcttttatta cattagttaa gatgtctgag agaccatctc ctatctttta tttcattcat atcctccgcc ctttttgtcc tagagtgaga gtttggaagg tgtccaaatt taatgtagac attatctttt ggctctgaag aagcaaacat gactagagac gcaccttgct gcagtgtcca gaagcggcct gtgcgttccc ttcagtactg cagcgccacc cagtggaagg acactcttgg ctcgtttggg ctcaaggcac cgcagcctgt cagccaacat tgccttgcat ttgtacctta ttgatctttg cccatggaag tctcaaagat ctttcgttgg ttgtttctct gagctttgtt actgaaatga gcctcgtggg gagcatcaga gaaggccagg aagaatggtg tgtttcccta gactctgtaa ccacctctct gtctttttcc ttcctgagaa acgtccatct ctctccctta ctattcccac tttcattcaa tcaacctgca cttcatatct agatttctag aaaagcttcc tagcttatct ccctgcttca tatctctccc ttctttacct tcatttcatc ctgttggctg ctgccaccaa atctgtctag aatcctgctt tacaggatca tgtaaatgct caaagatgta atgtagttct ttgttcctgc tttctctttc agtattaaac tctcctttga tattatgtgg cttttatttc agtgccatac atgttattgt tttcaaccta gaaaccttta tccctgctta tctgaaactt cccaacttcc ctgttcttta agactttttt tttttttttt tttttttttg agacagagtc tcgctctgtc gcccaggctg gagggcagtg gcacgatctc agctcactgc aagctccaac tcccgggttc acgccattct cctgcctcag ccttccaagt agctgggact acaggtgccc gccaccgtgc ccggctaatt tttttgtatt tttagtagag acagggtttc accatgttag ccgggatggt cttgatctcc tgacctcatg atccacccac ctcagcctcc caaagtgttg ggattacagg cgtgagccac tgcgcccggg caagaccttt ttttaaaaaa aaaaaaaaaa aaacttccat tctttcttcc tccagtctgt tctcacataa cagagtagtt ttggttttta attttttttg gttgtttgct gttttttgtt ttttaaggtg agttctcact atgtttctca gactggtctc gaactcctgg cctcaagcca tcttcccgcc tcagcctctc aaatagctgg gcttacaggc atgagccacc acacctggcc aggatttggt tgtttaaata taaatctgat cacccccctg cttagaaccc ttctgctttc tattacccct catttaaaat gtaaactctt caccttggtt tatgagaact ggttcttgcc ttccccttga acctcattaa atggtgattt cttgctaagc tccagcccga gtggtctcct ctcagcttct aattttgtgc tctttcctgc ccttttcctg ggccttctca gctctccacc cccaccactc ttgactcagg tggtgtcctt cttcctcaag tcttgacaat tcccgggccc ttcagtccct gagcagtcta cttctgtgtc tgtcaccaca tcttgtcttt tcccctcatt gcatttattg cagtttatat atatgctact tttacttgtt catttctgtc tcccctacca ggctgtaaat gagggcagaa accttgtttg ttttattcac catcatgtac caagtgcttg gcacatagtg ggccttcatt aaatgtttgt tgaataaaag agggaagaag gcaagccaac cttagctaca atcctacctt ttgataaaat gttccttttg acaatataca cggattatta tttgtacttt gtttttccat gtgttttgct tttatccact ggcattttta gctccttgaa gacatatcat gtgtgagata acttccttca catctcccat ggtccctagc aaaatgctag gcctgtagta gtcaaggtgc tcaataaata tttgtttggg tggtttgtga gccttgctgc caagtcctgc ctttgggtcg acatagtatg gaagtatttg agagagagaa cctttccact cccactgcca ggattttgta ttgccatcgg gtgccaaata aatgctcata tttattaaaa aaaaaaaaaa aaaaa SEQ ID NO: 78 Homo sapiens caspase 2, apoptosis-related cysteine peptidase (neural precursor cell expressed, developmentally down-regulated 2) (CASP2) (NP_116764.2) MAAPSAGSWSTFQHKELMAADRGRRILGVCGMHPHHQETLKKNRVVLAKQLLLSELLEHLLEKDIITLEMRELIQ AKVGSFSQNVELLNLLPKRGPQAFDAFCEALRETKQGHLEDMLLTTLSGLQHVLPPLSCDYDLSLPFPVCESCPL YKKLRLSTDTVEHSLDNKDGPVCLQVKPCTPEFYQTHFQLAYRLQSRPRGLALVLSNVHFTGEKELEFRSGGDVD HSTLVTLFKLLGYDVHVLCDQTAQEMQEKLQNFAQLPAHRVTDSCIVALLSHGVEGAIYGVDGKLLQLQEVFQLF DNANCPSLQNKPKMFFIQACRGDETDRGVDQQDGKNHAGSPGCEESDAGKEKLPKMRLPTRSDMICGYACLKGTA AMRNTKRGSWYIEALAQVFSERACDMHVADMLVKVNALIKDREGYAPGTEFHRCKEMSEYCSTLCRHLYLFPGHP PT SEQ ID NO: 79 Homo sapiens killer cell immunoglobulin-like receptor, two domains, short cytoplasmic tail, 1 (KIR2DS1) (NM_014512) caccggcagc accatgtcgc tcacggtcgt cagcatggcg tgtgttgggt tcttcttgct gcagggggcc tggccacatg agggagtcca cagaaaacct tccctcctgg cccacccagg tcgcctggtg aaatcagaag agacagtcat cctgcaatgt tggtcagatg tcatgtttga acacttcctt ctgcacagag aggggatgtt taacgacact ttgcgcctca ttggagaaca ccatgatggg gtctccaagg ccaacttctc catcagtcgc atgaagcaag acctggcagg gacctacaga tgctacggtt ctgttactca ctccccctat cagttgtcag ctcccagtga ccctctggac atcgtgatca taggtctata tgagaaacct tctctctcag cccagccggg ccccacggtt ctggcaggag agaatgtgac cttgtcctgc agctcccgga gctcctatga catgtaccat ctatccaggg aaggggaggc ccatgaacgt aggctccctg cagggaccaa ggtcaacgga acattccagg ccaactttcc tctgggccct gccacccatg gagggaccta cagatgcttc ggctctttcc gtgactctcc atacgagtgg tcaaagtcaa gtgacccact gcttgtttct gtcacaggaa acccttcaaa tagttggcct tcacccactg aaccaagctc cgaaaccggt aaccccagac acctacatgt tctgattggg acctcagtgg tcaaaatccc tttcaccatc ctcctcttct ttctccttca tcgctggtgc tccgacaaaa aaaatgctgc tgtaatggac caagagcctg cagggaacag aacagtgaac agcgaggatt ctgatgaaca agaccatcag gaggtgtcat acgcataatt ggatcactgt gttttcacac agagaaaaat cactcgccct tctgagaggc ccaagacacc cccaacagat accagcatgt acatagaact tccaaatgct gagcccagat ccaaagttgt cttctgtcca cgagcaccac agtcaggcct tgaggggatc ttctagggag a SEQ ID NO: 80 Homo sapiens killer cell immunoglobulin-like receptor, two domains, short cytoplasmic tail, 1 (KIR2DS1)(NP_055327.1) MSLTVVSMACVGFFLLQGAWPHEGVHRKPSLLAHPGRLVKSEETVILQCWSDVMFEHFLLHREGMFNDTLRLIGE HHDGVSKANFSISRMKQDLAGTYRCYGSVTHSPYQLSAPSDPLDIVIIGLYEKPSLSAQPGPTVLAGENVTLSCS SRSSYDMYHLSREGEAHERRLPAGTKVNGTFQANFPLGPATHGGTYRCFGSFRDSPYEWSKSSDPLLVSVTGNPS NSWPSPTEPSSETGNPRHLHVLIGTSVVKIPFTILLFFLLHRWCSDKKNAAVMDQEPAGNRTVNSEDSDEQDHQE VSYA SEQ ID NO: 81 Homo sapiens mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2)(NM_004579) cagagccacg ggcgcccgcc ccgccccgcg ccgccccgcg ccggctccgc agctcgcgcc cgcccgcctg ccggcccgcc cggcgccggg ccatggcgct gctgcgggat gtgtcgctgc aggacccgcg ggaccgcttc gagctgctgc agcgcgtggg ggccgggacc tatggcgacg tctacaaggc ccgcgacacg gtcacgtccg aactggccgc cgtgaagata gtcaagctag acccagggga cgacatcagc tccctccagc aggaaatcac catcctgcgt gagtgccgcc accccaatgt ggtggcctac attggcagct acctcaggaa tgaccgcttg tggatctgca tggagttctg cggagggggc tccctgcagg agatttacca tgccactggg cccctggagg agcggcagat tgcctacgtc tgccgagagg cactgaaggg gctccaccac ctgcattctc aggggaagat ccacagagac atcaagggag ccaaccttct cctcactctc cagggagatg tcaaactggc tgactttggg gtgtcaggcg agctgacagc gtctgtggcc aagaggaggt ctttcattgg gactccctac tggatggctc ccgaggtggc tgctgtggag cgcaaaggtg gctacaatga gctatgtgac gtctgggccc tgggcatcac tgccattgag ctgggcgagc tgcagccccc tctgttccac ctgcacccca tgagggccct gatgctcatg tcgaagagca gcttccagcc gcccaaactg agagataaga ctcgctggac ccagaatttc caccactttc tcaaactggc cctgaccaag aatcctaaga agaggccgac agcagagaag ctcctgcagc acccgttcac gactcagcag ctccctcggg ccctcctcac acagctgctg gacaaagcca gtgaccctca tctggggacc ccctcccctg aggactgtga gctggagacc tatgacatgt ttccagacac cattcactcc cgggggcagc acggcccagc cgagaggacc ccctcggaga tccagtttca ccaggtgaaa tttggcgccc cacgcaggaa ggaaactgac ccactgaatg agccgtggga ggaagagtgg acactactgg gaaaggaaga gttgagtggg agcctgctgc agtcggtcca ggaggccctg gaggaaagga gtctgactat tcggtcagcc tcagaattcc aggagctgga ctccccagac gataccatgg gaaccatcaa gcgggccccg ttcctagggc cactccccac tgaccctcca gcagaggagc ctctgtccag tcccccagga accctgcccc cacctccttc aggccccaac agctccccac tgctgcccac ggcctgggcc accatgaagc agcgggagga tcctgagagg tcatcctgcc acgggctccc cccaactccc aaggtgcata tgggcgcctg cttctccaag gtcttcaatg gctgccccct gcggatccac gctgctgtca cctggattca ccctgttact cgggaccagt tcctggtggt aggggccgag gaaggcatct acacactcaa cctgcatgaa ctgcatgagg atacgctgga gaagctgatt tcacatcgct gctcctggct ctactgcgtg aacaacgtgc tgctgtcact ctcagggaaa tccacgcaca tctgggccca tgacctccca ggcctgtttg agcagcggag gctacagcaa caggttcccc tctccatccc caccaaccgc ctcacccagc gcatcatccc caggcgcttt gctctgtcca ccaagattcc tgacaccaaa ggctgcttgc agtgtcgtgt ggtgcggaac ccctacacgg gtgccacctt cctgctggcc gccctgccca ccagcctgct cctgctgcag tggtatgagc cgctgcagaa gtttctgctg ctgaagaact tctccagccc tctgcccagc ccagctggga tgctggagcc gctggtgctg gatgggaagg agctgccgca ggtgtgtgtt ggggccgagg ggcctgaggg gcccggctgc cgcgtcctgt tccatgtcct gcccctggag gctggcctga cgcccgacat cctcatccca cctgagggga tcccaggctc ggcccagcag gtgatccagg tggacaggga cacaatccta gtcagctttg aacgctgtgt gaggattgtc aacatgcagg gcgagcccac ggccacactg gcacctgagc tgacctttga tttccccatc gagactgtgg tgtgcctgca ggacagtgtg ctggccttct ggagccatgg gatgcaaggc cgaagcctgg ataccaatga ggtgacccag gagatcacag atgaaacaag gatcttccga gtgcttgggg cccacagaga catcatcctg gagagcattc ccactgacaa cccagaggcg cacagcaacc tctacatcct cacgggccac cagagcacct actaagagca gcgggcctgt ccaggggctc cccgccccac cccacgcctt agctgcaggc ccttttgggc aaaggggccc atcctagacc agaggagccc aggccctggc cctgctgggg ctgaaggtca gaagtaatcc tgagaaatgt ttcaggcctg gggagggagg ggagcccccg acgcctctgc aataactgga ccagggggag ctgctgtcac tcccccatcc ccgaggcagc ccagtcccta gtgcccaagg cagggaccct gggcctgggc catccattcc attttgttcc acatttcctt tctactcttt ctgccaagag cctgcccctg catttgtcct gggaaacacg gtatttaaga gagaactata ttggtattaa agctggtttg ttttaaaaaa aaaa SEQ ID NO: 82 Homo sapiens mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2)(NP_004570.2) MALLRDVSLQDPRDRFELLQRVGAGTYGDVYKARDTVTSELAAVKIVKLDPGDDISSLQQEITILRECRHPNVVA YIGSYLRNDRLWICMEFCGGGSLQEIYHATGPLEERQIAYVCREALKGLHHLHSQGKIHRDIKGANLLLTLQGDV KLADFGVSGELTASVAKRRSFIGTPYWMAPEVAAVERKGGYNELCDVWALGITAIELGELQPPLFHLHPMRALML MSKSSFQPPKLRDKTRWTQNFHHFLKLALTKNPKKRPTAEKLLQHPFTTQQLPRALLTQLLDKASDPHLGTPSPE DCELETYDMFPDTIHSRGQHGPAERTPSEIQFHQVKFGAPRRKETDPLNEPWEEEWTLLGKEELSGSLLQSVQEA LEERSLTIRSASEFQELDSPDDTMGTIKRAPFLGPLPTDPPAEEPLSSPPGTLPPPPSGPNSSPLLPTAWATMKQ REDPERSSCHGLPPTPKVHMGACFSKVFNGCPLRIHAAVTWIHPVTRDQFLVVGAEEGIYTLNLHELHEDTLEKL ISHRCSWLYCVNNVLLSLSGKSTHIWAHDLPGLFEQRRLQQQVPLSIPTNRLTQRIIPRRFALSTKIPDTKGCLQ CRVVRNPYTGATFLLAALPTSLLLLQWYEPLQKFLLLKNFSSPLPSPAGMLEPLVLDGKELPQVCVGAEGPEGPG CRVLFHVLPLEAGLTPDILIPPEGIPGSAQQVIQVDRDTILVSFERCVRIVNMQGEPTATLAPELTFDFPIETVV CLQDSVLAFWSHGMQGRSLDTNEVTQEITDETRIFRVLGAHRDIILESIPTDNPEAHSNLYILTGHQSTY SEQ ID NO: 83 Homo sapiens chemokine (C—X—C motif) ligand 5 (CXCL5)(NM_002994) gtgcagaagg cacgaggaag ccacagtgct ccggatcctc caatcttcgc tcctccaatc tccgctcctc cacccagttc aggaacccgc gaccgctcgc agcgctctct tgaccactat gagcctcctg tccagccgcg cggcccgtgt ccccggtcct tcgagctcct tgtgcgcgct gttggtgctg ctgctgctgc tgacgcagcc agggcccatc gccagcgctg gtcctgccgc tgctgtgttg agagagctgc gttgcgtttg tttacagacc acgcaaggag ttcatcccaa aatgatcagt aatctgcaag tgttcgccat aggcccacag tgctccaagg tggaagtggt agcctccctg aagaacggga aggaaatttg tcttgatcca gaagcccctt ttctaaagaa agtcatccag aaaattttgg acggtggaaa caaggaaaac tgattaagag aaatgagcac gcatggaaaa gtttcccagt cttcagcaga gaagttttct ggaggtctct gaacccaggg aagacaagaa ggaaagattt tgttgttgtt tgtttatttg tttttccagt agttagcttt cttcctggat tcctcacttt gaagagtgtg aggaaaacct atgtttgccg cttaagcttt cagctcagct aatgaagtgt ttagcatagt acctctgcta tttgctgtta ttttatctgc tatgctattg aagttttggc aattgactat agtgtgagcc aggaatcact ggctgttaat ctttcaaagt gtcttgaatt gtaggtgact attatatttc caagaaatat tccttaagat attaactgag aaggctgtgg atttaatgtg gaaatgatgt ttcataagaa ttctgttgat ggaaatacac tgttatcttc acttttataa gaaataggaa atattttaat gtttcttggg gaatatgtta gagaatttcc ttactcttga ttgtgggata ctatttaatt atttcacttt agaaagctga gtgtttcaca ccttatctat gtagaatata tttccttatt cagaatttct aaaagtttaa gttctatgag ggctaatatc ttatcttcct ataattttag acattcttta tctttttagt atggcaaact gccatcattt acttttaaac tttgatttta tatgctattt attaagtatt ttattaggag taccataatt ctggtagcta aatatatatt ttagatagat gaagaagcta gaaaacaggc aaattcctga ctgctagttt atatagaaat gtattctttt agtttttaaa gtaaaggcaa acttaacaat gacttgtact ctgaaagttt tggaaacgta ttcaaacaat ttgaatataa atttatcatt tagttataaa aatatatagc gacatcctcg aggccctagc atttctcctt ggatagggga ccagagagag cttggaatgt taaaaacaaa acaaaacaaa aaaaaacaag gagaagttgt ccaagggatg tcaatttttt atccctctgt atgggttaga ttttccaaaa tcataatttg aagaaggcca gcatttatgg tagaatatat aattatatat aaggtggcca cgctggggca agttccctcc ccactcacag ctttggcccc tttcacagag tagaacctgg gttagaggat tgcagaagac gagcggcagc ggggagggca gggaagatgc ctgtcgggtt tttagcacag ttcatttcac tgggattttg aagcatttct gtctgaatgt aaagcctgtt ctagtcctgg tgggacacac tggggttggg ggtgggggaa gatgcggtaa tgaaaccggt tagtcagtgt tgtcttaata tccttgataa tgctgtaaag tttattttta caaatatttc tgtttaagct atttcacctt tgtttggaaa tccttccctt ttaaagagaa aatgtgacac ttgtgaaaag gcttgtagga aagctcctcc ctttttttct ttaaaccttt aaatgacaaa cctaggtaat taatggttgt gaatttctat ttttgctttg tttttaatga acatttgtct ttcagaatag gattctgtga taatatttaa atggcaaaaa caaaacataa ttttgtgcaa ttaacaaagc tactgcaaga aaaataaaac atttcttggt aaaaacgtat gtatttatat attatatatt tatatataat atatattata tatttagcat tgctgagctt tttagatgcc tattgtgtat cttttaaagg ttttgaccat tttgttatga gtaattacat atatattaca ttcactatat taaaattgta cttttttact atgtgtctca ttggttcata gtctttattt tgtcctttga ataaacatta aaagatttct aaacttcaaa aaaaaaaaaa aaaaa SEQ ID NO: 84 Homo sapiens chemokine (C—X—C motif) ligand 5 (CXCL5)(NP_002985.1) MSLLSSRAARVPGPSSSLCALLVLLLLLTQPGPIASAGPAAAVLRELRCVCLQTTQGVHPKMISNLQVFAIGPQC SKVEVVASLKNGKEICLDPEAPFLKKVIQKILDGGNKEN SEQ ID NO: 85 Homo sapiens chemokine (C—X—C motif) ligand 3 (CXCL3)(NM_002090) gctccgggaa tttccctggc ccggccgctc cgggctttcc agtctcaacc atgcataaaa agggttcgcc gatcttgggg agccacacag cccgggtcgc aggcacctcc ccgccagctc tcccgcttct cgcacagctt cccgacgcgt ctgctgagcc ccatggccca cgccacgctc tccgccgccc ccagcaatcc ccggctcctg cgggtggcgc tgctgctcct gctcctggtg gccgccagcc ggcgcgcagc aggagcgtcc gtggtcactg aactgcgctg ccagtgcttg cagacactgc agggaattca cctcaagaac atccaaagtg tgaatgtaag gtcccccgga ccccactgcg cccaaaccga agtcatagcc acactcaaga atgggaagaa agcttgtctc aaccccgcat cccccatggt tcagaaaatc atcgaaaaga tactgaacaa ggggagcacc aactgacagg agagaagtaa gaagcttatc agcgtatcat tgacacttcc tgcagggtgg tccctgccct taccagagct gaaaatgaaa aagagaacag cagctttcta gggacagctg gaaaggactt aatgtgtttg actatttctt acgagggttc tacttattta tgtatttatt tttgaaagct tgtattttaa tattttacat gctgttattt aaagatgtga gtgtgtttca tcaaacatag ctcagtcctg attatttaat tggaatatga tgggttttaa atgtgtcatt aaactaatat ttagtgggag accataatgt gtcagccacc ttgataaatg acagggtggg gaactggagg gtggggggat tgaaatgcaa gcaattagtg gatcactgtt agggtaaggg aatgtatgta cacatctatt ttttatactt tttttttaaa aaaagaatgt cagttgttat ttattcaaat tatctcacat tatgtgttca acatttttat gctgaagttt cccttagaca ttttatgtct tgcttgtagg gcataatgcc ttgtttaatg tccattctgc agcgtttctc tttcccttgg aaaagagaat ttatcattac tgttacattt gtacaaatga catgataata aaagttttat gaaaaaaaaa aaaaaa SEQ ID NO: 86 Homo sapiens chemokine (C—X—C motif) ligand 3 (CXCL3)(NP_002081.2) MAHATLSAAPSNPRLLRVALLLLLLVAASRRAAGASVVTELRCQCLQTLQGIHLKNIQSVNVRSPGPHCAQTEVI ATLKNGKKACLNPASPMVQKIIEKILNKGSTN SEQ ID NO: 87 Homo sapiens chemokine (C-C motif) ligand 13 (CCL13)(NM_005408) aaaaggccgg cggaacagcc agaggagcag agaggcaaag aaacattgtg aaatctccaa ctcttaacct tcaacatgaa agtctctgca gtgcttctgt gcctgctgct catgacagca gctttcaacc cccagggact tgctcagcca gatgcactca acgtcccatc tacttgctgc ttcacattta gcagtaagaa gatctccttg cagaggctga agagctatgt gatcaccacc agcaggtgtc cccagaaggc tgtcatcttc agaaccaaac tgggcaagga gatctgtgct gacccaaagg agaagtgggt ccagaattat atgaaacacc tgggccggaa agctcacacc ctgaagactt gaactctgct acccctactg aaatcaagct ggagtacgtg aaatgacttt tccattctcc tctggcctcc tcttctatgc tttggaatac ttctaccata attttcaaat aggatgcatt cggttttgtg attcaaaatg tactatgtgt taagtaatat tggctattat ttgacttgtt gctggtttgg agtttatttg agtattgctg atcttttcta aagcaaggcc ttgagcaagt aggttgctgt ctctaagccc ccttcccttc cactatgagc tgctggcagt gggtttgtat tcggttccca ggggttgaga gcatgcctgt gggagtcatg gacatgaagg gatgctgcaa tgtaggaagg agagctcttt gtgaatgtga ggtgttgcta aatatgttat tgtggaaaga tgaatgcaat agtaggactg ctgacatttt gcagaaaata cattttattt aaaatctcct aaaaaaaaaa a SEQ ID NO: 88 Homo sapiens chemokine (C-C motif) ligand 13 (CCL13)(NP_005399.1) MKVSAVLLCLLLMTAAFNPQGLAQPDALNVPSTCCFTFSSKKISLQRLKSYVITTSRCPQKAVIFRTKLGKEICA DPKEKWVQNYMKHLGRKAHTLKT SEQ ID NO: 89 Homo sapiens alpha-fetoprotein (AFP)(NM_001134) tccatattgt gcttccacca ctgccaataa caaaataact agcaaccatg aagtgggtgg aatcaatttt tttaattttc ctactaaatt ttactgaatc cagaacactg catagaaatg aatatggaat agcttccata ttggattctt accaatgtac tgcagagata agtttagctg acctggctac catatttttt gcccagtttg ttcaagaagc cacttacaag gaagtaagca aaatggtgaa agatgcattg actgcaattg agaaacccac tggagatgaa cagtcttcag ggtgtttaga aaaccagcta cctgcctttc tggaagaact ttgccatgag aaagaaattt tggagaagta cggacattca gactgctgca gccaaagtga agagggaaga cataactgtt ttcttgcaca caaaaagccc actccagcat cgatcccact tttccaagtt ccagaacctg tcacaagctg tgaagcatat gaagaagaca gggagacatt catgaacaaa ttcatttatg agatagcaag aaggcatccc ttcctgtatg cacctacaat tcttctttgg gctgctcgct atgacaaaat aattccatct tgctgcaaag ctgaaaatgc agttgaatgc ttccaaacaa aggcagcaac agttacaaaa gaattaagag aaagcagctt gttaaatcaa catgcatgtg cagtaatgaa aaattttggg acccgaactt tccaagccat aactgttact aaactgagtc agaagtttac caaagttaat tttactgaaa tccagaaact agtcctggat gtggcccatg tacatgagca ctgttgcaga ggagatgtgc tggattgtct gcaggatggg gaaaaaatca tgtcctacat atgttctcaa caagacactc tgtcaaacaa aataacagaa tgctgcaaac tgaccacgct ggaacgtggt caatgtataa ttcatgcaga aaatgatgaa aaacctgaag gtctatctcc aaatctaaac aggtttttag gagatagaga ttttaaccaa ttttcttcag gggaaaaaaa tatcttcttg gcaagttttg ttcatgaata ttcaagaaga catcctcagc ttgctgtctc agtaattcta agagttgcta aaggatacca ggagttattg gagaagtgtt tccagactga aaaccctctt gaatgccaag ataaaggaga agaagaatta cagaaataca tccaggagag ccaagcattg gcaaagcgaa gctgcggcct cttccagaaa ctaggagaat attacttaca aaatgcgttt ctcgttgctt acacaaagaa agccccccag ctgacctcgt cggagctgat ggccatcacc agaaaaatgg cagccacagc agccacttgt tgccaactca gtgaggacaa actattggcc tgtggcgagg gagcggctga cattattatc ggacacttat gtatcagaca tgaaatgact ccagtaaacc ctggtgttgg ccagtgctgc acttcttcat atgccaacag gaggccatgc ttcagcagct tggtggtgga tgaaacatat gtccctcctg cattctctga tgacaagttc attttccata aggatctgtg ccaagctcag ggtgtagcgc tgcaaacgat gaagcaagag tttctcatta accttgtgaa gcaaaagcca caaataacag aggaacaact tgaggctgtc attgcagatt tctcaggcct gttggagaaa tgctgccaag gccaggaaca ggaagtctgc tttgctgaag agggacaaaa actgatttca aaaactcgtg ctgctttggg agtttaaatt acttcagggg aagagaagac aaaacgagtc tttcattcgg tgtgaacttt tctctttaat tttaactgat ttaacacttt ttgtgaatta atgaaatgat aaagactttt atgtgagatt tccttatcac agaaataaaa tatctccaaa tg SEQ ID NO: 90 Homo sapiens alpha-fetoprotein (AFP)(NP_005399.1) MKWVESIFLIFLLNFTESRTLHRNEYGIASILDSYQCTAEISLADLATIFFAQFVQEATYKEVSKMVKDALTAIE KPTGDEQSSGCLENQLPAFLEELCHEKEILEKYGHSDCCSQSEEGRHNCFLAHKKPTPASIPLFQVPEPVTSCEA YEEDRETFMNKFIYEIARRHPFLYAPTILLWAARYDKIIPSCCKAENAVECFQTKAATVTKELRESSLLNQHACA VMKNFGTRTFQAITVTKLSQKFTKVNFTEIQKLVLDVAHVHEHCCRGDVLDCLQDGEKIMSYICSQQDTLSNKIT ECCKLTTLERGQCIIHAENDEKPEGLSPNLNRFLGDRDFNQFSSGEKNIFLASFVHEYSRRHPQLAVSVILRVAK GYQELLEKCFQTENPLECQDKGEEELQKYIQESQALAKRSCGLFQKLGEYYLQNAFLVAYTKKAPQLTSSELMAI TRKMAATAATCCQLSEDKLLACGEGAADIIIGHLCIRHEMTPVNPGVGQCCTSSYANRRPCFSSLVVDETYVPPA FSDDKFIFHKDLCQAQGVALQTMKQEFLINLVKQKPQITEEQLEAVIADFSGLLEKCCQGQEQEVCFAEEGQKLI SKTRAALGV SEQ ID NO: 91 Homo sapiens C-type lectin domain 4, member E (CLEC4E) (NM_014358) atattctaca tctatcggag ctgaacttcc taaaagacaa agtgtttatc tttcaagatt cattctccct gaatcttacc aacaaaacac tcctgaggag aaagaaagag agggagggag agaaaaagag agagagagaa acaaaaaacc aaagagagag aaaaaatgaa ttcatctaaa tcatctgaaa cacaatgcac agagagagga tgcttctctt cccaaatgtt cttatggact gttgctggga tccccatcct atttctcagt gcctgtttca tcaccagatg tgttgtgaca tttcgcatct ttcaaacctg tgatgagaaa aagtttcagc tacctgagaa tttcacagag ctctcctgct acaattatgg atcaggttca gtcaagaatt gttgtccatt gaactgggaa tattttcaat ccagctgcta cttcttttct actgacacca tttcctgggc gttaagttta aagaactgct cagccatggg ggctcacctg gtggttatca actcacagga ggagcaggaa ttcctttcct acaagaaacc taaaatgaga gagtttttta ttggactgtc agaccaggtt gtcgagggtc agtggcaatg ggtggacggc acacctttga caaagtctct gagcttctgg gatgtagggg agcccaacaa catagctacc ctggaggact gtgccaccat gagagactct tcaaacccaa ggcaaaattg gaatgatgta acctgtttcc tcaattattt tcggatttgt gaaatggtag gaataaatcc tttgaacaaa ggaaaatctc tttaagaaca gaaggcacaa ctcaaatgtg taaagaagga agagcaagaa catggccaca cccaccgccc cacacgagaa atttgtgcgc tgaacttcaa aggacttcat aagtatttgt tactctgata taaataaaaa taagtagttt taaatgttat aattcatgtt actggctgaa gtgcattttc tctctacgtt agtctcaggt cctcttccca gaatttacaa agcaattcac taccttttgc tacatttgcc tcatttttta gtgttcgtat gaaagtacag ggacacggag ccaagacaga gtctagcaaa gaaggggatt ttggaaggtg ccttccaaaa atctcctgaa tccgggctct gtagcaggtc ctcttctttc tagcttctga caagtctgtc ttctcttctt ggtttcatac cgttcttatc tcctgcccaa gcatatatcg tctctttact cccctgtata atgagtaaga agcttcttca agtcatgaaa cttattcctg ctcagaatac cggtgtggcc tttctggcta caggcctcca ctgcaccttc ttagggaagg gcatgccagc catcagctcc aaacaggctg taaccaagtc cacccatccc tggggcttcc tttgctctgc cttattttca attgactgaa tggatctcac cagattttgt atctattgct cagctaggac ccgagtccaa tagtcaattt attctaagcg aacattcatc tccacacttt cctgtctcaa gcccatccat tatttcttaa cttttatttt agctttcggg ggtacatgtt aaaggctttt tatataggta aactcatgtc gtggaggttt gttgtacaga ttatttcatc acccaggtat taagcccagt gcctaatatt gtttttttcg gctcctctcc ctcctcctac cttccgccct caagtagact ccagtgtctg ttattccctt ctttgtgttt atgaattctc atcatttagc tcccacttat aagtgaggac atgcagtatt tggttttctg ttcccatgtt tgctaaggat aatggtttcc agttctaccg atgttcccac aaaagacata attttctttt ttaaggctgc ttagtattcc atggtatcta tgtatcacat tttctctatc caatctattg ttgactcaca tttagattga ttccatgttt ttgctattgt gaatagtgct gcaatgaaca ttcgtgtgca tgtgtcttta tggtagaaag atttatattt ctctgagtat gtatccagta atagcccatt catttattgc ataaaattct accaatac SEQ ID NO: 92 Homo sapiens C-type lectin domain 4, member E (CLEC4E) (NP_055173) MNSSKSSETQCTERGCFSSQMFLWTVAGIPILFLSACFITRCVVFRIFQTCDEKKFQLPENFTELSCYNYGSGSV KNCCPLNWEYFQSSCYFFSTDTISWALSLKNCSAMGAHLVVINSQEEQEFLSYKKPKMREFFIGLSDQVVEGQWQ WVDGTPLTK SLSFWDVGEPNNIATLEDCATMRDSSNPRQNWNDVTCFLNYFRICEMVGINPLNKGKSL 

1. A method of providing a prognosis of Parkinson's disease in a subject treated with intravenous immunoglobulin (IVIG), the method comprising the steps of: (a) contacting a biological sample from the subject treated with IVIG with a reagent that specifically binds to at least one marker selected from the group consisting of the nucleic acid and corresponding protein sequences shown in Table 3a, Table 3b, and Table 4; and (b) determining whether or not the marker is overexpressed or underexpressed in the sample; thereby providing a prognosis for Parkinson's disease in a subject treated with IVIG.
 2. The method of claim 1, wherein the reagent is an antibody.
 3. The method of claim 2, wherein the antibody is monoclonal.
 4. The method of claim 1, wherein the reagent is a nucleic acid.
 5. The method of claim 1, wherein the reagent is an RT PCR primer set.
 6. The method of claim 1, wherein the sample is a blood sample.
 7. The method of claim 6, wherein the blood sample comprises T cells.
 8. The method of claim 1, wherein the sample is cerebrospinal fluid.
 9. The method of claim 1, wherein said at least one marker is a chemokine.
 10. The method of claim 9, wherein said chemokine is selected from the group consisting of CXCL3, CXCL5, CCL13, and XCL2.
 11. A method of identifying a compound that prevents or treats Parkinson's disease, the method comprising the steps of: (a) contacting a compound with a sample comprising a cell that expresses a marker selected from the group consisting of the nucleic acid and corresponding protein sequences shown in Table 3a, Table 3b, Table 3c, Table 3d, and Table 4; and (b) determining the functional effect of the compound on the marker, thereby identifying a compound that prevents or treats Parkinson's disease.
 12. The method of claim 11, wherein the functional effect is an increase or decrease in expression of the marker.
 13. The method of claim 11, wherein the functional effect is an increase or decrease in activity of the marker.
 14. The method of claim 11, wherein the compound is a small molecule.
 15. The method of claim 11, wherein the compound is a siRNA.
 16. The method of claim 11, wherein the compound is a ribozyme.
 17. The method of claim 11, wherein the compound is an antibody.
 18. A method of treating or preventing Parkinson's disease in a subject, the method comprising the step of administering to said subject an effective amount of an antibody which binds a chemokine selected from the group consisting of CXCL5, CXCL3, and CCL13, wherein said effective amount is sufficient to inactivate chemokine cell signaling, thereby treating or preventing Parkinson's disease.
 19. A method of treating or preventing Parkinson's disease in a subject, the method comprising the step of administering to said subject an effective amount of an antibody which binds a chemokine receptor selected from the group consisting of receptors for CXCL5, CXCL3, and CCL13, wherein said effective amount is sufficient to inactivate said chemokine receptor, thereby treating or preventing Parkinson's disease.
 20. A method of treating or preventing Parkinson's disease in a subject, the method comprising the step of administering to said subject an effective amount of an antibody which binds to a XCL2 chemokine receptor, wherein said effective amount is sufficient to activate said XCL2 chemokine receptor, thereby treating or preventing Parkinson's disease. 